Novel 1,3-dihydro-2H-indol-2-one derivatives, process for preparing them and pharmaceutical compositions containing them

ABSTRACT

The invention relates to compounds of formula:  
                 
 
and to solvates and/or hydrates thereof, with affinity for and selectivity towards the V 1b  receptors or both the V 1b  and V 1a  receptors of arginine-vasopressin. 
The invention also relates to a process for preparing them, to the intermediate compounds of formula (II) which are useful for preparing them, to pharmaceutical compositions containing them and to their use for preparing medicinal products.

The present invention relates to novel 1,3-dihydro-2H-indol-2-onederivatives, to a process for preparing them and to pharmaceuticalcompositions containing them.

The compounds according to the present invention have affinity for andselectivity towards the V_(1b) receptors or both the V_(1b) and V_(1a)receptors of arginine-vasopressin (AVP).

AVP is a hormone which is known for its anti-diuretic effect and itseffect in regulating arterial pressure. It stimulates several types ofreceptors: V₁ (V_(1a), V_(1b)), V₂. These receptors are located inparticular in the liver, the blood vessels (coronary, renal and cerebralvessels), the platelets, the kidneys, the uterus, the adrenal glands,the pancreas, the central nervous system and the pituitary. AVP thusexerts cardiovascular, hepatic, pancreatic, antidiuretic andplatelet-aggregating effects and effects on the central and peripheralnervous system, and on the uterus.

The location of the various receptors is described in: S. Jard et al.,Vasopressin and oxytocin receptors: an overview, in Progress inEndocrinology, H. Imura and K. Shizurne ed., Experta Medica, Amsterdam,1988, 1183-1188, and in the following articles: J. Lab. Clin. Med.,1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.

More particularly, the AVP V_(1a) receptors are located in manyperipheral organs and in the brain. They have been cloned in rats andman and they regulate most of the known effects of AVP: plateletaggregation; uterine contractions; blood vessel contraction; secretionof aldosterone, cortisol, CRF (corticotropin-releasing factor) and ACTH(adrenocorticotrophic hormone); hepatic glycogenolysis, cellproliferation and the main central effects of AVP (hypothermia, memory,etc.).

The V_(1b) receptors were initially identified in the adenohypophysis ofvarious animal species (rat, pig, cattle, sheep, etc.), including man(S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic etal., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al.,Endocrinology, 1991, 129 (2), 1107-1109; Y. De Keyser et al., FEBSLetters, 1994, 356, 215-220) in which they stimulate the release ofadenocorticotrophic hormone via AVP and potentiate the effects of CRF onthe release of ACTH (G. E. Gillies et al., Nature, 1982, 299, 355). Inthe hypothalamus, the V_(1b) receptors also induce a direct release ofCRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these variousrespects, involved in stress conditions.

These V_(1b) receptors have been cloned in rats, man and mice (Y. DeKeyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol.Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem. Biophys.Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al., Neurobiology,1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecularendocrinology, 1999, 22, 251-260) and various studies (in situhybridization, PCR (Polymerase Chain Reaction), etc.) reveal theubiquitous presence of these receptors in various central tissues(brain, hypothalamus and adenohypophysis in particular) and peripheraltissues (kidney, pancreas, adrenal glands, heart, lungs, intestine,stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina,thyroid, etc.) and in certain tumours (pituitary, pulmonary, etc.tumours) suggesting a broad biological and/or pathological role forthese receptors and a potential involvement in various diseases.

By way of example, in rats, studies have shown that AVP regulates theendocrine pancreas via the V_(1b) receptors, by stimulating thesecretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 269(Endocrinol. Metab. 32): E1095-E1100, 1995) or the production ofcatecholamines in the adrenal medullary which is the site of a localsynthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a),3906-3914). Thus, in the medullary tissue, AVP via these receptors isthought to have a crucial role in certain types of adrenalpheochromocytomas secreting AVP and thereby inducing a sustainedproduction of catecholamines which is the cause of hypertensionconditions that are resistant to angiotensin II receptor antagonists andto conversion enzyme inhibitors. The adrenal cortex is also rich inV_(1a) receptors involved in the production of glucocorticoids andmineralocorticoids (aldosterone and cortisol). Via these receptors, AVP(circulating or synthesized locally) may induce a production ofaldosterone with an efficacy comparable to that of angiotensin II (G.Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol is apowerful regulator of the production of ACTH, the stress hormone.

Recent studies have also shown that the adrenal glands are capable ofreleasing CRF and/or ACTH directly via activation of the V_(1b) and/orV_(1a) receptors borne by the medullary cells (G. Mazzocchi et al.,Peptides, 1997, 18 (2), 191-195; E. Grazzini et al., J. Clin.Endocrinol. Metab., 1999, 84 (6), 2195-2203).

The V_(1b) receptors are also considered as a marker of ACTH-secretingtumours such as certain pituitary tumours, certain bronchial carcinomas(SCLCs (Small-Cell Lung Cancers)), pancreatic, adrenal and thyroidcarcinomas, inducing Cushing's syndrome in certain cases (J. Bertheratet al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wittert et al.,Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endorcinol.Metab., 1996, 81 (8), 2934-2941). As regards the Via receptors, theseare a marker more specific for small-cell lung cancers (SCLCs) (P. J.Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73).Thus, the compounds according to the present invention are obviousdiagnostic tools and offer a novel therapeutic approach in theproliferation and detection of these tumours, even at an early stage(radiolabelling; SPECT (Single Photon Emission Computed Tomography); PETScan (Positron Emission Tomography Scanner)).

The abundant presence of the V_(1b) receptor messenger in the stomachand intestine suggests an involvement of AVP via this receptor on therelease of gastrointestinal hormones such as choleocystokinin, gastrinor secretin (T. Sugimoto et al., Molecular cloning and functionalexpression of V_(1b) receptor gene, in Neurohypophysis: Recent Progressof Vasopressin and Oxytocin Research; T. Saito, K. Kurokawa and S.Yoshida ed., Elvesier Science, 1995, 409-413).

1,3-Dihydro-2H-indol-2-one derivatives have been disclosed in certainpatent applications as ligands of the arginine-vasopressin receptorsand/or the ocytocin receptors: mention may be made of patentapplications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO97/15556 and WO 98/25901.

To date, no non-peptide compound with affinity for and selectivitytowards the V_(1b) receptors or both the V_(1b) and V_(1a) receptors ofarginine-vasopressin is known.

Novel 1,3-dihydro-2H-indol-2-one derivatives have now been found whichshow affinity for and selectivity towards the V_(1b) receptors or boththe V_(1b) and V_(1a) receptors of arginine-vasopressin.

These compounds may be used to prepare medicinal products that areuseful in treating or preventing any pathology in whicharginine-vasopressin and/or the V_(1b) receptors or both the V_(1b)receptors and the V_(1a) receptors are involved, in particular intreating or preventing complaints of the cardiovascular system, forexample hypertension; of the central nervous system, for example stress,anxiety, depression, obsessive-compulsive disorder and panic attacks; ofthe renal system; of the gastric system, and also in treating small-celllung cancers; obesity; type II diabetes; insulin resistance;hypertriglyceridaemia; atherosclerosis; Cushing's syndrome; anypathology resulting from stress and chronic stress conditions.

Thus, according to one of its aspects, the present invention relates tocompounds of formula:

in which:

-   -   n is 1 or 2;    -   W represents an oxygen atom or a sulphur atom;    -   R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a        trifluoromethyl radical; a trifluoromethoxy radical;    -   R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a        (C₁-C₄)alkoxy; a trifluoromethyl radical;    -   or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂        together represent a trimethylene radical;    -   R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a        (C₁-C₂)alkoxy; a trifluoromethoxy radical;    -   R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a        (C₁-C₂)alkoxy;    -   or R₃ is in position -2- of the phenyl, R₄ is in position -3- of        the phenyl and R₃ and R₄ together represent a methylenedioxy        radical;    -   R₅ represents an ethylamino group; a dimethylamino group; a        1-azetidinyl radical; a (C₁-C₂)alkoxy;    -   R₆ represents a (C₁-C₄)alkoxy;    -   R₇ represents a (C₁-C₄)alkoxy;        as well as the solvates and/or hydrates thereof.

The compounds of formula (I) comprise at least 2 asymmetric carbonatoms. The optically pure isomers of the compounds of formula (I) andthe mixtures thereof in all proportions form part of the invention.

The term “halogen atom” means a chlorine, bromine, fluorine or iodineatom.

The terms “alkyl” and “alkoxy”, respectively, mean a linear or branchedalkyl radical or alkoxy radical, respectively.

According to the present invention, the compounds of formula (I) thatare preferred are those in which:

-   -   n is 1 or 2;    -   W represents an oxygen atom or a sulphur atom;    -   R₁ represents a halogen atom; a (C₁-C₄)alkyl; a trifluoromethyl        radical; a tri-fluoromethoxy radical;    -   R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a        (C₁-C₄)alkoxy; a trifluoromethyl radical;    -   or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂        together represent a trimethylene radical;    -   R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkoxy; a        trifluoromethoxy radical;    -   R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a        (C₁-C₂)alkoxy;    -   or R₃ is in position -2- of the phenyl, R₄ is in position -3- of        the phenyl and R₃ and R₄ together represent a methylenedioxy        radical;    -   R₅ represents an ethylamino group; a dimethylamino group; a        1-azetidinyl radical; a (C₁-C₂)alkoxy;    -   R₆ represents a (C₁-C₄)alkoxy;    -   R₇ represents a (C₁-C₄)alkoxy;        as well as the solvates and/or hydrates thereof.

According to the present invention, the compounds of formula (I) thatare preferred are those in which W represents an oxygen atom.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₁ represents a chlorine atom, a methylradical or a trifluoromethoxy radical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₂ represents a hydrogen atom, achlorine atom, a fluorine atom, a methyl radical, a methoxy radical or atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-oneand, together with R₁, represents a trimethylene radical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₃ represents a chlorine atom, afluorine atom, a hydroxyl, a methoxy radical, an ethoxy radical or atrifluoromethoxy radical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₄ represents a hydrogen atom, amethoxy radical or a methyl radical; or R₄ is in position -3- of thephenyl and, together with R₃ in position 2, represents a methylenedioxyradical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₅ represents a dimethylamino group, anethylamino group, a 1-azetidinyl radical or a methoxy radical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₆ is in position -2- of the phenyl andrepresents a methoxy radical.

According to the present invention, the compounds of formula (I) thatare preferred are those in which R₇ represents a methoxy radical.

More particularly, the compounds of formula (I) that are preferred arethose in which:

-   -   n is 1 or 2;    -   W represents an oxygen atom;    -   R₁ represents a chlorine atom or a methyl radical;    -   R₂ represents a hydrogen atom or is in position -6- of the        indol-2-one and represents a chlorine atom, a methyl radical, a        methoxy radical or a trifluoromethyl radical;    -   R₃ is in position -2- of the phenyl and represents a methoxy        radical, a chlorine atom or a fluorine atom;    -   R₄ represents a hydrogen atom, a methyl radical or a methoxy        radical;    -   or R₃ is in position -2- of the phenyl, R₄ is in position -3- of        the phenyl and R₃ and R₄ together represent a methylenedioxy        radical;    -   R₅ represents a dimethylamino group or a methoxy radical;    -   R₆ is in position -2- of the phenyl and represents a methoxy        radical;    -   R₇ represents a methoxy radical;        as well as the solvates and/or hydrates thereof.

According to the present invention, the compounds of formula (I) in theform of optically pure isomers are preferred.

More particularly, the optically pure isomers of the compounds offormula:

in which n, W, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined for acompound of formula (I), the carbon atom bearing the substituent C(W)R₅has the (S) configuration and the carbon atom in position 3 of theindol-2-one has either the (R) configuration or the (S) configuration,are preferred.

Most particularly, the laevorotatory isomer of the compounds of formula(Ia) is preferred.

The following compounds:

-   -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,6-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[3-(1,3-Benzodioxol-4-yl)-5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-3-(2-fluorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxy-6-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[4,5-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5,6-Dimethyl-3-(2-methoxy-6-methylphenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,        laevorotatory isomer;    -   (2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,        laevorotatory isomer;    -   as well as the solvates and/or hydrates thereof, are more        particularly preferred.

According to another of its aspects, a subject of the present inventionis a process for preparing the compounds of formula (I), solvatesthereof and/or hydrates thereof, characterized in that:

-   -   a compound of formula:        in which n, W, R₁, R₂, R₃, R₄ and R₅ are as defined for a        compound of formula (I), is reacted, in the presence of a base,        with a halide of formula:        in which R₆ and R₇ are as defined for a compound of formula (I)        and Hal represents a halogen atom.

The reaction is carried out in the presence of a strong base, forinstance a metal hydride such as sodium hydride or an alkali metalalkoxide such as potassium tert-butoxide, in an anhydrous solvent suchas N,N-dimethylformamide or tetrahydrofuran and at a temperature ofbetween −70° C. and +60° C. The reaction is preferably carried out usinga compound of formula (III) in which Hal=Cl.

According to one variant of the process and when R₅ represents anethylamino group, a dimethylamino group or a 1-azetidinyl radical and Wrepresents an oxygen atom:

-   -   a) a compound of formula:        in which n, R₁, R₂, R₃ and R₄ are as defined for a compound of        formula (I), is reacted, in the presence of a base, with a        halide of formula:        in which R₆ and R₇ are as defined for a compound of formula (I),        to give a compound of formula:    -   b) the compound of formula (I′) is hydrolysed by the action of        an acid to give a compound of formula:    -   c) the compound of formula (I″) is reacted with ethylamine,        dimethylamine or azetidine.

In step a), the reaction between the compound of formula (II′) and thehalide of formula (III) is carried out as described above for theprocess according to the invention.

The compound of formula (I′) thus obtained is hydrolysed in step b) witha strong acid such as hydrochloric acid in an inert solvent such asdioxane and at a temperature of between 0° C. and room temperature.

In step c), the reaction between the compound of formula (I″) andethylamine, dimethylamine or azetidine is carried out in the presence ofa coupling agent used in peptide chemistry, such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate inthe presence of a base such as triethylamine orN,N-diisopropyl-ethylamine, in an inert solvent such as dichloromethane,tetrahydrofuran or a mixture of these solvents, and at a temperature ofbetween 0° C. and room temperature.

In particular, a compound of formula (I) in which R₃ represents hydroxylis prepared by reacting a compound of formula (II) in which R₃represents a benzyloxy group with a compound of formula (III) accordingto the process of the invention. The compound thus obtained is thendeprotected according to the method described in Chem. Pharm. Bull.,1978, 26 (8), 2562-2564 to give the expected compound of formula (I).

The compounds of formula (I) thus obtained may be subsequently separatedfrom the reaction medium and purified according to the conventionalmethods, for example by crystallization or chromatography.

The compounds of formula (II) or (II′) are prepared by reacting a3-halo-1,3-dihydro-2H-indol-2-one compound of formula:

in which R₁, R₂, R₃ and R₄ are as defined for a compound of formula (I)and Hal represents a halogen atom, preferably chlorine or bromine, witha compound of formula:

in which n, W and R₅ are as defined for a compound of formula (I). Thereaction is carried out in the absence or presence of a base such asdiisopropylethylamine or triethylamine, in an inert solvent such asdichloro-methane, chloroform, tetrahydrofuran, methanol or a mixture ofthese solvents and at a temperature of between 0° C. and the refluxtemperature of the solvent. In the absence of base, the reaction iscarried out using an excess of the compound of formula (V) or (V′).

The compounds of formula (III) are known or prepared by known methodssuch as those disclosed in EP-0 469 984 B and WO 95/18105. For example,the compounds of formula (III) may be prepared by halogenation of thecorresponding benzenesulphonic acids or of their salts, for example oftheir sodium or potassium salts. The reaction is carried out in thepresence of a halogenating agent such as phosphorus oxychloride, thionylchloride, phosphorus trichloride, phosphorus tribromide or phosphoruspentachloride, without solvent or in an inert solvent such as ahalogenated hydrocarbon or N,N-dimethylformamide and at a temperature ofbetween −10° C. and 200° C.

2,4-Dimethoxybenzenesulphonyl chloride is prepared according to J. Am.Chem. Soc., 1952, 74, 2008. 3,4-Dimethoxybenzenesulphonyl chloride iscommercially available, or is prepared according to J. Med. Chem., 1977,20 (10), 1235-1239.

The compounds of formula (IV) are known and are prepared according toknown methods such as those disclosed in WO 95/18105.

For example, a compound of formula:

in which R₁, R₂, R₃ and R₄ are as defined for a compound of formula (I),is converted into a compound of formula (IV) in which Hal=Cl by theaction of thionyl chloride in the presence of a base such as pyridine,in an inert solvent such as dichloromethane and at a temperature ofbetween 0° C. and room temperature.

According to another example of the preparation of the compounds offormula (IV), a compound of formula:

in which R₁, R₂, R₃ and R₄ are as defined for a compound of formula (I),is converted into a compound of formula (IV) in which Hal=Br, using ahalogenating agent such as bromine according to the process described inFarm. Zh. (Kiev), 1976, 5, 30-33.

The compounds of formula (VI) are known and are prepared according toknown methods such as those disclosed in WO 95/18105.

For example, a compound of formula (VI) is prepared by reacting a1H-indole-2,3-dione derivative of formula:

in which R₁ and R₂ are as defined for a compound of formula (I), with anorganomagnesium derivative of formula:

in which R₃ and R₄ are as defined for a compound of formula (I) and Halrepresents a halogen atom, preferably bromine or iodine, in an inertsolvent such as tetrahydrofuran or diethyl ether and at a temperature ofbetween 0° C. and the reflux temperature of the solvent.

A compound of formula (VI) in which R₃ is as defined for a compound offormula (I) and is in position -2- of the phenyl and R₄, which is otherthan hydrogen, is in position -3- or -6- of the phenyl, may also beprepared by reacting a compound of formula:

in which R₃ is as defined for a compound of formula (I) and R₄ is inposition -2- or -5- of the phenyl, with a lithium derivative such asn-butyllithium, and the lithiated intermediate thus obtained is thenreacted with a compound of formula (VIII). The reaction is carried outin a solvent such as diethyl ether, tetrahydrofuran, hexane or a mixtureof these solvents, at a temperature of between −70° C. and roomtemperature.

The 1H-indole-2,3-dione derivatives (VIII) are commercially available orare prepared according to the methods described in Tetrahedron Letters,1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35, 7303-7306; J. Org.Chem., 1977, 42 (8), 1344-1348; J. Org. Chem., 1952, 17, 149-156; J. Am.Chem. Soc., 1946, 68, 2697-2703; Organic Syntheses, 1925, V, 71-74 andAdvances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton,Academic Press, New York, 1975, 18, 2-58.

The organomagnesium derivatives (IX) are prepared according to theconventional methods that are well known to those skilled in the art.

A compound of formula (VI) may also be prepared by atmospheric oxidationof a compound of formula (VII) in the presence of a base such as sodiumhydride and in the presence of dimethyl disulphide.

In particular, the compounds of formula (VI) in which R₃ is in position-2 of the phenyl and R₃═(C₁-C₂)alkoxy and R₄═H, or R₃═R₄═(C₁-C₂)alkoxywith R₄ in position -3 or -6 of the phenyl, R₂ is other than a halogenatom and R₁ is as defined for a compound of formula (I), may be preparedby following the process described in Scheme 1.

In step a1 of Scheme 1, a compound of formula (X) is first reacted witha lithium derivative such as n-butyllithium, in the absence or presenceof a base such as N,N,N′,N′-tetramethylethylenediamine, and thelithiated intermediate thus obtained is then reacted with diethyloxalate to give the compound of formula (XI). The reaction is carriedout in an inert solvent such as diethyl ether, tetrahydrofuran, hexaneor a mixture of these solvents and at a temperature of between −70° C.and room temperature.

In step b1, a compound of formula (XII) is first reacted with twoequivalents of a lithium derivative such as tert-butyllithium, and thelithiated derivative thus obtained is then reacted with the compound offormula (XI) to give the expected compound of formula (VI). The reactionis carried out in an inert solvent such as diethyl ether,tetrahydrofuran, pentane or a mixture of these solvents and at atemperature of between −70° C. and room temperature.

The compounds of formula (X) are commercially available or aresynthesized conventionally.

The compounds of formula (XII) are prepared by reacting thecorresponding aniline derivatives with di-tert-butyl dicarbonateaccording to the conventional methods.

The compounds of formula (VII) are known and are prepared according toknown methods such as those disclosed in WO 95/18105 or in J. Org.Chem., 1968, 33, 1640-1643.

The compounds of formula (V) are known or are prepared according toknown methods. Thus, for example, the compounds of formula (V) in whichW represents an oxygen atom and R₅ represents an ethylamino ordimethylamino group or a 1-azetidinyl radical are prepared according toScheme 2 below in which Pr represents an N-protecting group, inparticular tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl and n is asdefined for a compound of formula (I).

In step a2 of Scheme 2, the nitrogen atom of the compound of formula(XIII) is protected according to the conventional methods to give acompound of formula (XIV). Some of the compounds of formula (XIV) arecommercially available.

The acid (XIV) is reacted in step b2 with ethylamine, dimethylamine orazetidine according to the conventional methods of peptide coupling togive the compound of formula (XV), which is deprotected in step c2,according to the known methods, to give the expected compound of formula(V). In particular, when Pr represents a 9-fluorenylmethoxycarbonylgroup, the deprotection is carried out using the method described inSynthetic Communications, 1994, 24 (2), 187-195.

The compounds of formula (V) in which R₅ represents a (C₁-C₂)alkoxy orthe compounds of formula (V′) are known or are prepared according toknown methods such as, for example, by esterification reaction startingwith the acids of formula (XIII).

The acids of formula (XIII) are commercially available.

The compounds of formula (V) in which W represents a sulphur atom areprepared from the corresponding compounds of formula (V) in which Wrepresents an oxygen atom, N-protected on the nitrogen atom, using themethods described in J. Med. Chem., 1989, 2178-2199, in particular byreaction with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulphide orwith phosphorus pentasulphide. After a step of deprotection of thenitrogen atom, the expected compound of formula (V) is obtained.

When it is desired to prepare an optically pure compound of formula (I),an optically pure compound of formula (II) or (II′) is preferablyreacted according to the process of the invention or the variant of theprocess.

The optically pure compounds of formula (II) or (II′) are prepared byreacting the racemic compound of formula (IV) with an optically purecompound of formula (V) or (V′), followed by separation of the mixtureof diastereoisomers according to the conventional methods, for exampleby crystallization or chromatography.

Alternatively, the mixture of diastereoisomers of the compound offormula (II) or (II′) may be reacted and the mixture of diastereoisomersof the compound of formula (I) thus obtained may be separated.

During any one of the steps for preparing the compounds of formula (I)or the intermediate compounds of formula (II), (II′), (IV), (V), (V′) or(VI), it may be necessary and/or desirable to protect the reactive orsensitive functional groups, such as the amine, hydroxyl or carboxylgroups, present on any one of the molecules concerned. This protectionmay be carried out using the conventional protecting groups, such asthose described in Protective Groups in Organic Chemistry, J. F. W.McOmie, Ed. Plenum Press, 1973, in Protective Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wutts, Ed. John Wiley and Sons,1991 or in Protecting Groups, Kocienski P. J., 1994, Georg ThiemeVerlag. The protecting groups may be removed by a suitable subsequentstep using the methods known to those skilled in the art which do notaffect the rest of the molecule concerned.

The N-protecting groups which may be used are the conventionalN-protecting groups that are well known to those skilled in the art,such as, for example, the tert-butoxycarbonyl,fluorenylmethoxy-carbonyl, benzyl, benzhydrylidene or benzyloxycarbonylgroup.

The compounds of formula (II) are novel and form part of the invention.

Thus, according to another of its aspects, a subject of the invention iscompounds of formula:

in which:

-   -   n is 1 or 2;    -   W represents an oxygen atom or a sulphur atom;    -   R₁ represents a halogen atom; a (C₁-C₄) alkyl; a (C₁-C₄)alkoxy;        a trifluoromethyl radical; a trifluoromethoxy radical;    -   R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄) alkyl;        a (C₁-C₄)alkoxy; a trifluoromethyl radical;    -   or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂        together represent a divalent trimethylene radical;    -   R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a        (C₁-C₂)alkoxy; a trifluoromethoxy radical;    -   R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a        (C₁-C₂)alkoxy;    -   or R₃ is in position -2- of the phenyl, R₄ is in position -3- of        the phenyl and R₃ and R₄ together represent a methylenedioxy        radical;    -   R₅ represents an ethylamino group; a dimethylamino group; a        1-azetidinyl radical; a (C₁-C₂)alkoxy;        as well as the salts thereof with mineral or organic acids, in        the form of optically pure isomers or in the form of a mixture        of diastereoisomers or in the form of a racemic mixture.

The salts of the compounds of formula (II) comprise those with mineralor organic acids which allow a suitable separation or crystallization ofthe compounds of formula (II) such as the hydrochloride, thehydrobromide, the oxalate, the maleate, the succinate, the fumarate, thecitrate or the acetate.

The above compounds of formula (I) also comprise those in which one ormore hydrogen or carbon atoms have been replaced with their radioactiveisotope, for example tritium, or carbon-14. Such labelled compounds areuseful in research, metabolism or pharmacokinetics studies and inbiochemical assays as receptor ligands.

The compounds according to the invention have undergone biochemicalstudies.

The affinity of the compounds of formula (I) according to the inventionfor arginine-vasopressin V_(1b) receptors was determined in vitro usingthe method described by Y. De Keyser et al., FEBS Letters, 1994, 356,215-220. This method consists in studying in vitro the displacement oftritiated arginine-vasopressin ([³H]-AVP) at the V_(1b) receptorspresent on adenohypophysal membrane or cell preparations carrying rat orhuman V_(1b) receptors. The 50% inhibitory concentrations (IC₅₀) for theattachment of tritiated arginine-vasopressin of the compounds accordingto the invention are low and vary from 10⁻⁷ to 10⁻⁹ M.

The affinity of the compounds of formula (I) according to the inventionfor arginine-vasopressin V_(1a) receptors was determined in vitro usingthe method described by M. Thibonnier et al., J. Biol. Chem., 1994, 269,3304-3310. This method consists in studying in vitro the displacement oftritiated arginine-vasopressin ([³H]-AVP) at the V_(1a) receptorspresent on membrane or cell preparations carrying rat or human V_(1a)receptors. Some of the compounds of formula (I) also exhibit an affinityfor arginine-vasopressin V_(1a) receptors, with IC₅₀ values which varyfrom 10⁻⁷ to 10⁻⁹ M.

The affinity of the compounds of formula (I) according to the inventionfor vasopressin V₂ receptors has also been studied (method described byM. Birnbaumer et al., Nature (Lond.), 1992, 357, 333-335). The compoundsstudied have little or no affinity for the V₂ receptors, with IC₅₀values which are generally greater than 10⁻⁶ M.

The compounds of the present invention are in particular activeprinciples of pharmaceutical compositions, the toxicity of which iscompatible with their use as medicaments.

According to another of its aspects, the present invention relates tothe use of the compounds of formula (I), of their solvates and/or oftheir hydrates which are pharmaceutically acceptable for the preparationof medicaments intended for the treatment of any pathology wherearginine-vasopressin and/or its V_(1b) receptors or both its V_(1b)receptors and its V_(1a) receptors are implicated.

According to another of its aspects, the present invention relates tothe use of the compounds of formula (I), of their solvates and/or oftheir hydrates which are pharmaceutically acceptable for the preparationof medicaments intended for the treatment of pathologies of thecardiovascular system, of the central nervous system, of the renalsystem or of the gastric system and of small-cell lung cancers, obesity,type II diabetes, insulin resistance, hypertriglyceridaemia,atherosclerosis, Cushing's syndrome or any pathology resulting fromstress and chronic stress conditions.

Thus, the compounds according to the invention may be used, in man or inanimals, in the treatment or prevention of various vasopressin-dependentconditions, such as cardiovascular conditions, for example hypertension,pulmonary hypertension, cardiac insufficiency, myocardial infarction orcoronary vasospasm, in particular in smokers, Raynaud's syndrome,unstable angina and PTCA (percutaneous transluminal coronaryangioplasty), cardiac ischaemia or haemostasis disturbances; conditionsof the central nervous system, such as migraine, cerebral vasospasm,cerebral haemorrhage, cerebral oedema, depression, anxiety, stress,obsessive-compulsive disorder, panic attacks, psychotic states or memorydisorders, for example; conditions of the renal system, such as renalvasospasm, necrosis of the renal cortex or nephrogenic diabetesinsipidus; conditions of the gastric system, such as gastric vasospasm,cirrhosis of the liver, ulcers or the pathology of vomiting, for examplenausea, including nausea due to chemotherapy or travel sickness; ordiabetic nephropathy. The compounds according to the invention can alsobe used in the treatment of disorders of sexual behaviour; in women, thecompounds according to the invention can be used to treat dysmenorrhoeaor premature labour. The compounds according to the invention can alsobe used in the treatment of small-cell lung cancers; hyponatremicencephalopathy; pulmonary syndrome; Ménière's disease; glaucoma;cataracts; obesity; type II diabetes; atherosclerosis; Cushing'ssyndrome; insulin resistance; or hypertriglyceridaemia; or inpost-operative treatments, in particular after abdominal surgery.

The compounds according to the invention can also be used in thetreatment or prevention of any pathology resulting from stress, such asfatigue and its syndromes, ACTH-dependent disorders, cardiac disorders,pain, modifications in gastric emptying, in faecal excretion (colitis,irritable bowel syndrome or Crohn's disease) or in acid secretion,hyperglycaemia, immunosuppression, inflammatory processes (rheumatoidarthritis and osteoarthritis), multiple infections, cancers, asthma,psoriasis, allergies and various neuropsychiatric disorders, such asanorexia nervosa, bulimia, mood disorders, depression, anxiety, sleepdisorders, panic states, phobias, obsession, disorders of painperception (fibromyalgia), neurodegenerative diseases (Alzheimer'sdisease, Parkinson's disease or Huntington's disease), substancedependence, haemorrhagic stress, muscle spasms or hypoglycaemia. Thecompounds according to the invention can also be used in the treatmentor prevention of chronic stress conditions, such as immunodepression,fertility disorders or dysfunctionings of thehypothalamo-pituitary-adrenal axis.

The compounds according to the invention can also be used aspsychostimulants, resulting in an increase in alertness or emotionalreactivity to the surroundings and making adaptation easier.

The above compounds of formula (I), their solvates and/or their hydrateswhich are pharmaceutically acceptable can be used at daily doses of 0.01to 100 mg per kilo of body weight of the mammal to be treated,preferably at daily doses of 0.1 to 50 mg/kg. In man, the dose canpreferably vary from 0.1 to 4 000 mg per day, more particularly from 0.5to 1 000 mg, depending upon the age of the subject to be treated or thetype of treatment: prophylactic or curative.

For their use as medicaments, the compounds of formula (I) are generallyadministered in dosage units. The said dosage units are preferablyformulated in pharmaceutical compositions in which the active principleis mixed with one or more pharmaceutical excipients.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions including, as active principle, acompound of formula (I), one of its solvates and/or one of its hydrateswhich are pharmaceutically acceptable.

In the pharmaceutical compositions of the present invention foradministration by the oral, sublingual, inhaled, subcutaneous,intramuscular, intravenous, transdermal, local or rectal route, theactive principles can be administered in single-dose administrationforms, as a mixture with conventional pharmaceutical vehicles, toanimals and human beings. The appropriate single-dose administrationforms comprise forms by the oral route, such as tablets, gelatincapsules, powders, granules and oral solutions or suspensions,sublingual and buccal administration forms, aerosols, topicaladministration forms, implants, subcutaneous, intramuscular,intravenous, intranasal or intraocular administration forms and rectaladministration forms.

When a solid composition is prepared in the form of tablets or gelatincapsules, a mixture of pharmaceutical excipients is added to themicronized or nonmicronized active principle, which mixture can becomposed of diluents, such as, for example, lactose, microcrystallinecellulose, starch or dicalcium phosphate, of binders, such as, forexample, polyvinylpyrrolidone or hydroxypropylmethylcellulose, ofdisintegrating agents, such as crosslinked polyvinylpyrrolidone orcrosslinked carboxymethyl-cellulose, of flow agents, such as silica ortalc, or of lubricants, such as magnesium stearate, stearic acid,glyceryl tribehenate or sodium stearylfumarate.

Wetting agents or surfactants, such as sodium lauryl sulphate,polysorbate 80 or poloxamer 188, can be added to the formulation.

The tablets can be prepared by various techniques: direct tabletting,dry granulation, wet granulation or hot-melt.

The tablets can be bare or sugar-coated (with sucrose, for example) orcoated with various polymers or other appropriate materials.

The tablets can have a flash, delayed or sustained release by preparingpolymeric matrices or by using specific polymers when forming the thinfilm.

The gelatin capsules may be soft or hard and may or may not be coatedwith a thin film, so as to have a flash, sustained or delayed activity(for example via an enteric form).

They can comprise not only a solid formulation formulated as above fortablets but also liquids or semi-solids.

A preparation in the form of a syrup or elixir can comprise the activeprinciple in conjunction with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben, as antiseptic, a flavouringagent and an appropriate colorant.

The water-dispersible powders or granules can comprise the activeprinciple as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, as well as withsweeteners or flavour enhancers.

For rectal administration, recourse is had to suppositories which areprepared with binders which melt at the rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, use is made ofaqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which comprise pharmacologically compatible dispersing agentsand/or solubilizing agents, for example propylene glycol.

Thus, to prepare an aqueous solution which can be injected by theintravenous route, use may be made of a cosolvent, such as, for example,an alcohol, such as ethanol, or a glycol, such as polyethylene glycol orpropylene glycol, and of a hydrophilic surfactant, such as polysorbate80 or poloxamer 188. To prepare an oily solution which can be injectedby the intramuscular route, the active principle can be dissolved with atriglyceride or a glyceryl ester.

For local administration, use may be made of creams, ointments, gels,eyewashes or sprays.

For transdermal administration, use may be made of patches inmultilaminar or reservoir form, in which the active principle can be inalcoholic solution, or sprays.

For administration by inhalation, use is made of an aerosol comprising,for example, sorbitan trioleate or oleic acid andtrichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane, freon substitutes or any other biologicallycompatible propellant gas; use may also be made of a system comprisingthe active principle, alone or in combination with an excipient, inpowder form.

The active principle can also be presented in the form of a complex witha cyclodextrin, for example α-, β- or γ-cyclodextrin or2-hydroxypropyl-β-cyclodextrin.

The active principle can also be formulated in the form of microcapsulesor microspheres, optionally with one or more vehicles or additives.

Use may be made of implants among the sustained-release forms of use inthe case of chronic treatments. These implants can be prepared in theform of an oily suspension or in the form of a suspension ofmicrospheres in an isotonic medium.

The active principle of formula (I) is present in each dosage unit inthe amounts suited to the daily doses envisaged. In general, each dosageunit is suitably adjusted according to the dosage and the type ofadministration provided, for example tablets, gelatin capsules and thelike, sachets, blisters, syrups and the like, or drops, so that such adosage unit comprises from 0.1 to 1 000 mg of active principle,preferably from 0.5 to 250 mg, which has to be administered one to fourtimes daily.

Although these dosages are examples of average situations, there may bespecific cases where higher or lower dosages are appropriate; suchdosages also form part of the invention. According to the usualpractice, the dosage appropriate to each patient is determined by thephysician according to the method of administration and the age, theweight and the response of the said patient.

The compositions of the present invention can comprise, in addition tothe compounds of formula (I), their solvates and/or their hydrates whichare pharmaceutically acceptable, other active principles which can be ofuse in the treatment of the disorders or diseases indicated above.

Thus, another subject-matter of the present invention is pharmaceuticalcompositions comprising several active principles in combination, one ofwhich is a compound according to the invention.

Thus, according to the present invention, pharmaceutical compositionscan be prepared which comprise a compound according to the invention incombination with a compound which has an effect on the CRF receptors.

The compounds according to the invention can also be used for thepreparation of compounds for veterinary use.

The following PREPARATIONS and EXAMPLES illustrate the inventionwithout, however, limiting it.

Use is made, in the Preparations and in the Examples, of the followingabbreviations:

-   -   ether: diethyl ether    -   iso ether: diisopropyl ether    -   DMF: N,N-dimethylformamide    -   THF: tetrahydrofuran    -   DCM: dichloromethane    -   EtOAc: ethyl acetate    -   TMEDA: N,N,N′,N′-tetramethylethylenediamine    -   DIPEA: diisopropylethylamine    -   TFA: trifluoroacetic acid    -   Boc: tert-butoxycarbonyl    -   Cbz: benzyloxycarbonyl    -   Bzl: benzyl    -   BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   PyBOP: benzotriazol-1-yloxytripyrrolidino-phosphonium        hexafluorophosphate    -   DCC: 1,3-dicyclohexylcarbodiimide    -   HOBT: 1-hydroxybenzotriazole hydrate    -   Ethyl ether: saturated solution of hydrogen chloride in diethyl        ether    -   M.p.: melting point    -   RT: room temperature    -   B.p.: boiling point    -   HPLC: high performance liquid chromatography.

The proton magnetic resonance spectra (¹H NMR) are recorded at 200 MHzin d₆-DMSO using the d₆-DMSO peak as reference. The chemical shifts δare expressed in parts per million (ppm). The signals observed areexpressed thus: s: singlet; bs: broad singlet; d: doublet; dd: doubleddoublet; t: triplet; dt: doubled triplet; q: quartet; up: unresolvedpeak; mt: multiplet.

PREPARATIONS

Preparations of the compounds of formula (IV).

Preparation 1.13,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; Hal=Cl

A) 5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is prepared according to the procedure disclosed in WO95/18105. A solution of 2-methoxyphenylmagnesium bromide is preparedfrom 16 g of magnesium in 35 ml of ether and from a solution of 124 g of1-bromo-2-methoxybenzene in 175 ml of ether. This solution is addeddropwise under an argon atmosphere to a mixture, cooled beforehand in anice bath, of 30 g of 5-chloro-1H-indole-2,3-dione in 250 ml of THF andthen the mixture is left stirring while allowing the temperature to riseto RT. After stirring for 1 hour at RT, the reaction mixture is slowlypoured into saturated NH₄Cl solution and the THF is evaporated off undervacuum. The precipitate formed is spin-filtered off and is washed withiso ether. 42 g of the expected product are obtained, which product isused without further purification in the following stage.

B) 3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is prepared according to the procedure disclosed in WO95/18105. A mixture of 9 g of the compound obtained in the precedingstage and 3.74 ml of pyridine in 100 ml of DCM is cooled to 0° C., asolution of 3.45 ml of thionyl chloride in 3 ml of DCM is added dropwiseover 3 minutes, and the mixture is left stirring for 30 minutes. Wateris added to the reaction mixture and the DCM is evaporated off undervacuum at RT. The precipitate formed is spin-filtered off, washed fourtimes with water and then with cold iso ether, and dried. 8.8 g of theexpected product are obtained.

Preparation 1.23,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₂CH₃; R₄═H; Hal=Cl

A) 1-Bromo-2-ethoxybenzene

A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphate and 170ml of 10% NaOH solution is refluxed for 2 hours. After cooling thereaction mixture to RT, it is extracted with EtOAc, the organic phase iswashed with 2N NaOH solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. 19.6 g of the expected product areobtained.

B) 5-Chloro-3-(2-ethoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

A solution of 2-ethoxyphenylmagnesium bromide is prepared from 2.2 g ofmagnesium in 10 ml of ether and from a solution of 16.5 g of thecompound obtained in the preceding step in 40 ml of ether. This solutionis added dropwise, under a nitrogen atmosphere, to a mixture of 5 g of5-chloro-1H-indole-2,3-dione in 20 ml of THF, while keeping thetemperature of the reaction medium below 35° C. After stirring for 2hours at RT, the reaction mixture is poured into 200 ml of 2N HCl andextracted with EtOAc, the organic phase is dried over Na₂SO₄ and thesolvents are evaporated off under vacuum. The residue is taken up in hotiso ether and left to recrystallize. The crystalline product formed isspin-filtered off, washed with iso ether and dried.

5.7 g of the expected product are obtained;

m.p. =251° C.

C) 3,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

1 ml of thionyl chloride is added at RT to a mixture of 3 g of thecompound obtained in the preceding step and 2 ml of pyridine in 50 ml ofDCM, and the mixture is left stirring for 1 hour at RT. The reactionmixture is chromatographed on silica gel, eluting with DCM. 2.4 g of theexpected product are obtained after crystallization from iso ether;

m.p. =198° C.

Preparation 1.33,5-Dichloro-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=3-OCH₃; R₄═H; Hal=Cl

A) 5-Chloro-3-hydroxy-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

A solution of 3-methoxyphenylmagnesium bromide is prepared from 3.5 g ofmagnesium in 10 ml of THF and from a solution of 25 g of1-bromo-3-methoxy-benzene in 40 ml of THF. This solution is addeddropwise, under a nitrogen atmosphere, to a mixture of 8 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF, while keeping thetemperature of the reaction medium below 40° C., followed by refluxingfor 1 hour. The reaction mixture is cooled to RT, poured into saturatedNH₄Cl solution and extracted with EtOAc, the organic phase is washedwith water and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. 9.1 g of the expected product are obtained aftercrystallization from hot iso ether; m.p.=212° C.

B) 3,5-Dichloro-3-(3-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 5 g of the compound obtained in the preceding step and 2 mlof pyridine in 20 ml of DCM is cooled to a temperature below 10° C., asolution of 1.65 ml of thionyl chloride in 10 ml of DCM is addeddropwise and the mixture is left stirring for 30 minutes at RT. Thereaction mixture is washed twice with water, the organic phase is driedover Na₂SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica gel, eluting with DCM. 3.1 g of theexpected product are obtained;

m.p.=170° C.

Preparation 1.43,5-Dichloro-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=4-OCH₃; R₄═H; Hal=Cl

A) 5-Chloro-3-hydroxy-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is prepared according to the procedure described in step Aof Preparation 1.3 starting with 3.5 g of magnesium, 25 g of1-bromo-4-methoxybenzene, 50 ml of THF and a mixture of 8 g of5-chloro-1H-indol-2,3-dione in 50 ml of THF. 9.3 g of the expectedproduct are obtained after crystallization from hot iso ether; m.p.=202°C.

B) 3,5-Dichloro-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

0.9 ml of thionyl chloride is added to a mixture of 2.5 g of thecompound obtained in the preceding step and 1 ml of pyridine in 30 ml ofDCM at a temperature below 20° C., and the mixture is left stirring for15 minutes. The reaction mixture is washed twice with water and driedover Na₂SO₄, and this solution is used without further purification inPreparations 3.9 and 3.10.

Preparation 1.53,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=3-OCH₃; Hal=Cl

A) Ethyl 2-(2,3-dimethoxyphenyl)-2-oxoacetate

A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether is cooledto −40° C., 250 ml of a 1.6 M solution of n-butyllithium in hexane areadded dropwise and the mixture is then left stirring for 24 hours whileallowing the temperature to return to RT. The reaction mixture is cooledto −20° C., 136 ml of diethyl oxalate are added rapidly and the mixtureis left stirring while allowing the temperature to return to RT. Afterstirring for 30 minutes at RT, the reaction mixture is poured intosaturated NH₄Cl solution, the phases are separated after settling hastaken place, the aqueous phase is extracted with ether, the combinedorganic phases are washed twice with water and dried over Na₂SO₄, andthe solvents are evaporated off under vacuum. The excess diethyl oxalateis removed by distillation under vacuum (b.p.=90° C. at 2 400 Pa). Theresulting crude product is chromatographed on silica gel, eluting with aheptane/iso ether mixture (90/10; v/v). 25 g of the expected product areobtained and are used without further purification in the followingstep.

B) 5-Chloro-3-hydroxy-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-onea) tert-Butyl 4-chlorophenylcarbamate

A mixture of 12.7 g of 4-chloroaniline and 22 g of di-tert-butyldicarbonate in 60 ml of dioxane is left stirring for 24 hours at RT. Thereaction mixture is concentrated under vacuum, the residue is taken upin pentane and the precipitate formed is spin-filtered off and dried.22.5 g of the expected product are obtained.

b) A mixture of 11.4 g of tert-butyl

4-chlorophenylcarbamate in 100 ml of ether is cooled to −40° C. under anatmosphere of dry nitrogen, 80 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise and the mixture is leftstirring at −20° C. for 3 hours. The reaction mixture is cooled to −40°C., a solution of 14 g of the compound obtained in step A in 50 ml ofTHF is added over 1 hour and the mixture is left stirring for 4 days atRT. The reaction mixture is poured into saturated NH₄Cl solution and theprecipitate formed is spin-filtered off and dried. 10.2 g of theexpected product are obtained and are used without further purificationin the following step.

C) 3,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

0.8 ml of pyridine is added, at RT, to a mixture of 2 g of the compoundobtained in step B in 50 ml of DCM, followed by addition of 1.2 ml ofthionyl chloride, and the mixture is left stirring until dissolved. Thereaction mixture is washed with 1N HCl solution and then twice withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v). 1.2 g of the expected product areobtained and are used without further purification.

Preparation 1.63,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=4-OCH₃; Hal=Cl

A) 5-Chloro-3-hydroxy-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A solution of 2,4-dimethoxyphenylmagnesium bromide is prepared startingwith 2.2 g of magnesium in 10 ml of THF and a solution of 18 g of1-bromo-2,4-dimethoxybenzene in 40 ml of THF. This solution is addeddropwise to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 50 ml ofTHF at a temperature of 30° C., followed by refluxing for 2 hours. Thereaction mixture is cooled to RT, poured into saturated NH₄Cl solutionand extracted with EtOAc, the organic phase is washed with water anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. 7.2 gof the expected product are obtained after crystallization from hot isoether.

B) 3,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 1.5 g of the compound obtained in the preceding step and0.4 ml of pyridine in 20 ml of DCM is cooled to a temperature below 10°C., 0.45 ml of thionyl chloride is added dropwise and the mixture isleft stirring for 15 minutes. The reaction mixture is washed twice withwater and dried over Na₂SO₄, and this solution is used without furtherpurification in Preparations 3.13 and 3.14.

Preparation 1.73,5-Dichloro-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=5-OCH₃; Hal=Cl.

A) 5-Chloro-3-hydroxy-3-(2,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A solution of 2,5-dimethoxyphenylmagnesium bromide is prepared startingwith 2.2 g of magnesium, 18 g of 1-bromo-2,5-dimethoxybenzene and 50 mlof ether. This solution is added dropwise to a mixture of 5 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF at a temperature below 30°C., and is then refluxed for 3 hours. After cooling to RT, the reactionmixture is poured into 1N HCl solution and extracted with EtOAc, theorganic phase is washed with water and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 7.1 g of the expected productare obtained after crystallization from hot iso ether.

B) 3,5-Dichloro-3-(2,5-diemthoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3 g of the compound obtained in the preceding step and 1.2ml of pyridine in 50 ml of DCM is cooled to a temperature below 20° C.,0.8 ml of thionyl chloride is added and the mixture is left stirring for1 hour. The reaction mixture is washed with water, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM. 1.9 g of theexpected product are obtained and are used without further purification.

Preparation 1.83,5-Dichloro-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=6-OCH₃; Hal=Cl

A) Ethyl 2-(2,6-dimethoxyphenyl)-2-oxoacetate

A mixture of 28 g of 1,3-dimethoxybenzene and 24.3 g of TMEDA in 400 mlof hexane is cooled to a temperature below 10° C., 132 ml of a 1.6 Msolution of n-butyllithium in hexane are added dropwise and the mixtureis left stirring for 30 minutes. The reaction mixture is cooled to 0°C., 140 ml of diethyl oxalate are added over 15 minutes and the mixtureis left stirring for 1 hour at RT. The reaction mixture is poured into amixture of concentrated HCl solution and ice and is extracted withEtOAc, the organic phase is washed with water and dried over Na₂SO₄, andthe solvent is evaporated off under vacuum. The excess diethyl oxalateis removed by distillation under vacuum (b.p.=90° C. at 2 400 Pa). Theresulting crude product is chromatographed on silica gel, eluting withheptane and then with DCM. 34.5 g of the expected product are obtained.

B) 5-Chloro-3-hydroxy-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 28.5 g of tert-butyl 4-chlorophenylcarbamate (obtained instep Ba) of Preparation 1.5) in 300 ml of ether is cooled to −40° C.,191 ml of a 1.5 M solution of tert-butyllithium in pentane are addeddropwise and the mixture is left stirring for 3 hours at −20° C. Thereaction mixture is cooled to −60° C., a solution of 34.5 g of thecompound obtained in the preceding step in 50 ml of THF is addeddropwise and the mixture is left stirring for 48 hours at RT. Thereaction mixture is poured into saturated NH₄Cl solution and extractedwith EtOAc, the organic phase is washed with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with a DCM/MeOHmixture (99/1; v/v). 8.7 g of the expected product are obtained aftercrystallization from iso ether; m.p.=182° C.

C) 3,5-Dichloro-3-(2,6-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

1 ml of thionyl chloride is added to a mixture of 4 g of the compoundobtained in the preceding step and 1.8 ml of pyridine in 250 ml of DCM,and the mixture is left stirring for 30 minutes at RT. The reactionmixture is washed with water, the organic phase is dried over Na₂SO₄ andthe solvent is evaporated off under vacuum. 1.8 g of the expectedproduct are obtained after crystallization from iso ether.

Preparation 1.93,5-Dichloro-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=3-OCH₃; R₄=5-OCH₃; Hal=Cl

A) 5-Chloro-3-hydroxy-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

This compound is prepared according to the procedure described in step Aof Preparation 1.6, starting with 1.2 g of magnesium, 9.5 g of1-bromo-3,5-dimethoxybenzene, 50 ml of THF and a solution of 3 g of5-chloro-1H-indole-2,3-dione in 50 ml of THF. 3.2 g of the expectedproduct are obtained after crystallization from iso ether; m.p.=191° C.

B) 3,5-Dichloro-3-(3,5-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3.2 g of the compound obtained in the preceding step and0.7 ml of pyridine in 100 ml of DCM is cooled to a temperature below 20°C., 0.7 ml of thionyl chloride is added and the mixture is left stirringfor 15 minutes. The reaction mixture is washed with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. 1.4 g of the expected product are obtained after crystallizationfrom iso ether; m.p.=157° C.

Preparation 1.103,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃+R₄=2,3-O—CH₂O—; Hal=Cl

A) 4-Bromo-1,3-benzodioxole

This compound is prepared according to the process described inTetrahedron Lett., 1995, 36, 6413-6414.

B)5-Chloro-3-(1,3-benzodioxol-4-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

A solution of 1,3-benzodioxol-4-ylmagnesium bromide is prepared startingwith 0.85 g of magnesium in 10 ml of THF and a solution of 6.7 g of thecompound obtained in the preceding step in 40 ml of THF. This solutionis added dropwise and at a temperature below 40° C. to a mixture of 3 gof 5-chloro-1H-indole-2,3-dione in 50 ml of THF and the resultingmixture is then left stirring for one hour. The reaction mixture ispoured into saturated NH₄Cl solution and extracted with EtOAc, theorganic phase is washed with water and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 1.12 g of the expected productare obtained after crystallization from DCM; m.p.=271° C.

C) 3,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

0.3 ml of thionyl chloride is added, at a temperature below 25° C., to amixture of 1.1 g of the compound obtained in the preceding step and 0.4ml of pyridine in 20 ml of DCM, and the mixture is left stirring for 30minutes. The reaction mixture is washed twice with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. 0.62 g of the expected product is obtained after crystallizationfrom DCM; m.p.=241° C.

Preparation 1.113,5-Dichloro-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCF₃; R₄═H; Hal=Cl

A)5-Chloro-3-hydroxy-3-(2-trifluoromethoxy-phenyl)-1,3-dihydro-2H-indol-2-one

A solution of 25 g of 1-bromo-2-trifluoro-methoxybenzene in 130 ml ofether is added dropwise to a mixture of 2.8 g of magnesium in 20 ml ofether, the reflux being maintained once it has started. At the end ofthe addition, the mixture is refluxed for one hour. A mixture of 7.5 gof 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at atemperature below 40° C., followed by refluxing for one hour. Aftercooling to RT, the reaction mixture is poured into an ice/concentratedHCl mixture and extracted with EtOAc, the organic phase is washed withwater and with 1N NaOH solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. 6.5 g of the expected product areobtained after crystallization from a DCM/iso ether mixture (20/80;v/v); m.p.=214° C.

B) 3,5-Dichloro-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

0.7 ml of thionyl chloride is added, at a temperature below 20° C., to amixture of 2.7 g of the compound obtained in the preceding step and 1 mlof pyridine in 20 ml of DCM, and the mixture is left stirring for onehour. The reaction mixture is washed twice with water, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated off under vacuum. 1.8g of the expected product are obtained after crystallization from isoether; m.p.=185° C.

Preparation 1.123-Bromo-5-chloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-F; R₄═H; Hal=Br

A) D,L-2-Fluoromandelic Acid

This compound is prepared according to the process described in J. Org.Chem., 1968, 33, 2565-2566. This compound may also be prepared byfollowing the procedure below. A mixture of 17.4 g of2-fluorobenzaldehyde and 9.6 g of potassium cyanide in 30 ml of ether iscooled to a temperature below 10° C., 15 ml of concentrated HCl areadded over 30 minutes and the mixture is left stirring for 2 hours atRT. After separation of the phases by settling, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Thecrude product thus obtained is taken up in 20 ml of concentrated HCl andrefluxed for 5 hours. After cooling to RT, the reaction mixture isextracted with ether, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. 17.5 g ofthe expected product are obtained after crystallization from iso ether.

B) N-p-Chlorophenyl-D,L-2-fluoromandelamide

A mixture of 17.5 g of the compound obtained in the preceding step and13 g of p-chloroaniline in 100 ml of 1,2-dichlorobenzene is refluxed for3 hours, while removing the water formed using Dean-Stark apparatus.After cooling to RT, the mixture is left to crystallize. The precipitateformed is spin-filtered off and dissolved in EtOAc, the organic phase iswashed twice with 4N HCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. 16.2 g of the expected product areobtained after crystallization from iso ether.

C) 5-Chloro-3-(2-fluorophenyl)-1,3-dihydroindol-2-one

16.1 g of the compound obtained in the preceding step are added to amixture of 64 ml of concentrated (95%) H₂SO₄ and 16 ml of fumingsulphuric acid (30% oleum) at RT, and the mixture is then left stirringfor 8 hours. The reaction mixture is poured into a mixture of ice/waterand extracted with EtOAc, the organic phase is washed twice with waterand dried over Na₂SO₄ and the solvent is evaporated off under vacuum.12.2 g of the expected product are obtained after crystallization fromiso ether.

D) 3-Bromo-5-chloro-3-(2-fluorophenyl)-1,3-dihydro-2H-indol-2-one

A solution of 0.78 ml of bromine in 20 ml of chloroform is added slowlyat RT to a solution of 4 g of the compound obtained in the precedingstep in 100 ml of chloroform. The reaction mixture is concentrated undervacuum to give 4 g of the expected product after crystallization fromiso ether.

Preparation 1.133,5-Dichloro-3-(2-benzyloxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OBzl; R₄═H; Hal=Cl

A) 1-Bromo-2-benzyloxybenzene

A mixture of 35 g of 1-bromo-2-hydroxy-benzene, 30.5 g of benzylchloride and 50 g of K₂CO₃ in 500 ml of acetone is refluxed for 12hours. The reaction mixture is concentrated under vacuum, the residue istaken up in a water/EtOAc mixture, the organic phase is washed with 1NNaOH solution and with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The resulting oil is distilled underreduced pressure to give 50.3 g of the expected product, b.p.=155° C. at40 Pa.

B) 5-Chloro-3-(2-benzyloxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

A solution of 50 g of the compound obtained in the preceding step in 80ml of THF is added dropwise to a mixture of 5.1 g of magnesium in 20 mlof THF, the reflux being maintained once it has started. At the end ofthe addition, the mixture is refluxed for 3 hours. This solution is thenadded dropwise, at a temperature below 40° C., to a mixture of 13 g of5-chloro-1H-indole-2,3-dione in 100 ml of THF and the resulting mixtureis then refluxed for 2 hours. After cooling to RT, the reaction mixtureis poured into saturated NH₄Cl solution precooled on an ice bath, and isextracted with EtOAc, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis taken up in iso ether and left to crystallize. The precipitate formedis spin-filtered off and washed with boiling iso ether. 16.1 g of theexpected product are obtained; m.p.=197° C.

C) 3,5-Dichloro-3-(2-benzyloxyphenyl)-1,3-dihydro-2H-indol-2-one

0.4 ml of thionyl chloride is added, at a temperature below 20° C., to asolution of 1.35 g of the compound obtained in the preceding step and0.6 ml of pyridine in 30 ml of DCM, and the mixture is left stirring for30 minutes. The reaction mixture is washed with water, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated off under vacuum.1.18 g of the expected product are obtained after crystallization fromiso ether.

Preparation 1.143,5-Dichloro-3-(2-methoxy-6-methylphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=6-CH₃; Hal=Cl

A)5-Chloro-3-hydroxy-3-(2-methoxy-6-methylphenyl)-1,3-dihydro-2H-indol-2-one

A solution of 2-methoxy-6-methylphenyl-magnesium bromide is preparedstarting with 2.2 g of magnesium in 10 ml of THF and a solution of 16 gof 1-bromo-2-methoxy-6-methylbenzene in 40 ml of THF. This solution isadded dropwise at RT to a mixture of 6 g of 5-chloro-1H-indole-2,3-dionein 50 ml of THF and the resulting mixture is then refluxed for 1 hour.After cooling to RT, the reaction mixture is poured into 200 ml of 3NHCl solution and extracted with EtOAc, the organic phase is washed withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. 5.7 g of the expected product are obtained after crystallizationfrom iso ether.

B) 3,5-Dichloro-3-(2-methoxy-6-methylphenyl)-1,3-dihydro-2H-indol-2-one

A mixture of 3 g of the compound obtained in the preceding step and 1 mlof pyridine in 20 ml of DCM is cooled to a temperature below 10° C., 1.3g of thionyl chloride are added and the mixture is left stirring for 30minutes at RT. The reaction mixture is washed with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. 1 g of the expected product is obtained after crystallizationfrom iso ether.

Preparation 1.153-Chloro-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

(IV): R₁═OCF₃; R₂═H; R₃=2-OCH₃; R₄═H; Hal=Cl

A)3-Hydroxy-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

A solution of 2-methoxyphenylmagnesium bromide is prepared starting with1.9 g of magnesium in 4 ml of ether and a solution of 14.54 g of1-bromo-2-methoxybenzene in 21 ml of ether. This solution is addeddropwise, under an argon atmosphere, to a mixture of 5 g of5-trifluoromethoxy-1H-indole-2,3-dione in 26 ml of THF, precooled on anice bath, the resulting mixture is then heated at the reflux temperatureof the ether for 1 hour 30 minutes and is allowed to cool to RT. Thereaction mixture is poured slowly into saturated NH₄Cl solution andextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. 2.8 g of theexpected product are obtained.

B)3-Chloro-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

A mixture of 1 g of the compound obtained in the preceding step in 10 mlof DCM is cooled to 0° C., 0.24 ml of pyridine and then 0.22 ml ofthionyl chloride are added and the mixture is left stirring for 15minutes. This solution is used in this form in Preparation 3.30.

Preparation 1.163,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=6-Cl; R₃=2-OCH₃; R₄═H; Hal=

A) 5,6-Dichloro-1H-indole-2,3-dione

This compound is prepared according to the procedure described in J. Am.Chem. Soc., 1946, 68, 2697-2703 or according to the procedure describedin J. Org. Chem., 1952, 17, 149-156.

B) 5,6-Dichloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

5.57 g of 1-bromo-2-methoxybenzene are added dropwise to a suspension of0.72 g of magnesium in 15 ml of ether containing a few crystals ofiodine, the reflux being maintained once it has started. At the end ofthe addition, the mixture is refluxed for 2 hours. A suspension of 2.7 gof 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THF is then added andthe mixture is refluxed for 30 minutes. After cooling to RT, thereaction mixture is poured into a water/ice/concentrated HCl mixture andextracted with EtOAc, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is slurried in hotiso ether and the precipitate formed is spin-filtered off and washedwith ether. 3 g of the expected product are obtained.

C) 3,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

A suspension of 1.5 g of the compound obtained in the preceding step in30 ml of DCM is cooled on an ice bath and 0.56 ml of pyridine is added,followed by 0.5 ml of thionyl chloride. After stirring for 1 hour at RT,the reaction mixture is diluted by adding DCM, the organic phase iswashed with water to neutral pH and dried over Na₂SO₄, and the solventis evaporated off under vacuum. 1.5 g of the expected product areobtained in the form of a foam, which is used without furtherpurification.

Preparation 1.173-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=6-Cl; R₃=2-Cl; R₄═H; Hal=Br

A) N-3,4-Dichlorophenyl-D,L-2-chloromandelamide

This compound is prepared according to the procedure described in step Bof Preparation 1.12, starting with 3,4-dichloroaniline andD,L-2-chloromandelic acid; m.p.=160-163° C.

B) 5,6-Dichloro-3-(2-chlorophenyl)-1,3-dihydro-indol-2-one

A mixture of 53 ml of concentrated sulphuric acid and 12 ml of fumingsulphuric acid (30% oleum) is cooled to 0° C. and 13 g of the compoundobtained in the preceding step are added portionwise. The mixture isleft stirring for 24 hours at RT, the reaction mixture is poured intowater and the precipitate formed is spin-filtered off. The precipitateis dissolved in EtOAc, the organic phase is washed with water to pH 7and dried over sodium sulphate, and the solvent is partially evaporatedoff under vacuum. The crystalline product formed is spin-filtered offand recrystallized from a THF/DCM/EtOAc mixture. 1.3 g of the expectedproduct are obtained; m.p. 198-201° C.

C) 3-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 0.32 g of bromine in 1 ml of chloroform is added dropwiseto a suspension of 1.95 g of the compound obtained in the preceding stepin 30 ml of chloroform, and the mixture is left stirring for 30 minutesat RT. The reaction mixture is concentrated under vacuum, the residue istaken up in DCM and the solvent is evaporated off under vacuum. Theresidue is extracted with EtOAc, the organic phase is washed with waterto pH 7 and dried over sodium sulphate, and the solvent is evaporatedoff under vacuum. The expected product is obtained after crystallizationfrom DCM; m.p.=215-218° C.

Preparation 1.183-Bromo-4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=4-Cl; R₃=2-Cl; R₄═H; Hal=Br

A) 5,6-Dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one and4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

The process is performed as in step B of Preparation 1.17, starting with93 g of N-3,4-dichloro-phenyl-D,L-2-chloromandelamide. Afterspin-filtration of the precipitate formed corresponding to5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one, thespin-filtration liquor is concentrated under vacuum to give a mixture ofthe two expected products, which is used without further purification.

B) 3-Bromo-4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

A solution of 1.71 ml of bromine in 10 ml of DCM is added dropwise at RTto a suspension of 11.55 g of the mixture of compounds obtained in thepreceding step in 200 ml of DCM, and, at the end of the addition, afurther 0.38 ml of bromine is added. The reaction mixture isconcentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with water and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a gradient of the DCM/EtOAc mixture. Thefollowing are obtained:

-   -   the compound of Preparation 1.17 eluted with a DCM/EtOAc mixture        (88/12; v/v).

¹H NMR: d₆-DMSO: δ (ppm): 7.1: 2s: 2H; 7.5: up: 3H; 8.3: dd: 1H; 11.5:bs: 1H.

-   -   the compound of Preparation 1.18 eluted with a DCM/EtOAc mixture        (76/24; v/v).

¹H NMR: d₆-DMSO: δ (ppm): 7.2: d: 1H; 7.5: up: 4H; 8.3: dd: 1H; 11.5:bs: 1H.

Preparation 1.193,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=6-CH₃; R₃=2-OCH₃; R₄═H; Hal=Cl

A) Ethyl 2-(2-methoxyphenyl)-2-oxoacetate

A solution of 27 g of 1-bromo-2-methoxy-benzene in 270 ml of ether iscooled to −70° C. under an argon atmosphere, 90 ml of a 1.6 M solutionof n-butyl-lithium in pentane are added dropwise and the mixture is thenleft stirring for 45 minutes. 78 ml of diethyl oxalate are added rapidlyand the mixture is left stirring, while allowing the temperature toreturn to RT. After stirring for 1 hour at RT, saturated NH₄Cl solutionis added to the mixture, the phases are separated after settling hastaken place, the aqueous phase is extracted with ether, the combinedorganic phases are washed with water and then with saturated NaClsolution and dried over Na₂SO₄, and the solvents are evaporated offunder vacuum. The excess diethyl oxalate is removed by distillationunder vacuum (b.p.=87° C. at 2 000 Pa). The resulting product ischromatographed on silica gel, eluting with a DCM/hexane mixture (50/50;v/v) and then with DCM. The product obtained is purified by distillationunder vacuum. 13 g of the expected product are obtained; b.p.=110° C. at3 Pa.

B)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-onea) tert-Butyl 4-chloro-3-methylphenylcarbamate

A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g ofdi-tert-butyl dicarbonate in 50 ml of dioxane is left stirring for 24hours at RT. The reaction mixture is concentrated under vacuum and theresidue is chromatographed on silica gel, eluting with a gradient of aDCM/hexane mixture of from (50/50; v/v) to (70/30; v/v). 5.6 g of theexpected product are obtained and are used without further purification.

b) A solution of 5 g of tert-butyl 4-chloro-3-methylphenylcarbamate in45 ml of ether is cooled to −70° C. under an argon atmosphere, 30 ml ofa 1.5M solution of tert-butyllithium in pentane are added dropwise, themixture is left stirring for 1 hour while allowing the temperature torise to −10° C., and is left stirring for 1 hour 45 minutes at −10° C.The reaction mixture is cooled to −70° C., a solution of 5 g of thecompound obtained in step A in 25 ml of THF is added dropwise and themixture is left stirring for 1 hour while allowing the temperature torise to −30° C., and is then stirred overnight while allowing thetemperature to rise to RT. Saturated NH₄Cl solution is added to thereaction mixture, the THF is evaporated off, the resulting aqueous phaseis extracted three times with EtOAc, the organic phase is washed withwater, with saturated NaCl solution and dried over Na₂SO₄, the solventis partially evaporated off and the crystalline product is spin-filteredoff. 2.6 g of the expected product are obtained; m.p.=254-256° C.

C) 3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

A mixture of 2.0 g of the compound obtained in step B in 45 ml of DCM iscooled to 0° C., 0.77 ml of pyridine and then 1.17 g of thionyl chlorideare added and the mixture is left stirring for 2 hours after thetemperature has been allowed to return to RT. Water and DCM are added tothe reaction mixture and, after separation of the phases by settling,the organic phase is washed four times with water and dried over Na₂SO₄,and the solvent is evaporated off under vacuum. The expected product isobtained and is used without further purification.

Preparation 1.203,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=6-OCH₃; R₃=2-Cl; R₄═H; Hal=Cl

A) 4-Chloro-3-methoxyaniline

A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel® in 150 mlof MeOH and 200 ml of THF is hydrogenated in Parr apparatus for 4 hours,at 35° C. and under a pressure of 1.3 bar. The catalyst is filtered offover Celite® and the filtrate is concentrated under vacuum. 28 g of theexpected product are obtained and are used without further purification.

B) N-(4-Chloro-3-methoxyphenyl)-D,L-2-chloromandelamide

A mixture of 28 g of the compound obtained in the preceding step and33.13 g of D,L-2-chloromandelic acid in 128 ml of 1,2-dichlorobenzene isheated at 230° C. for 4 hours, while removing the water formed usingDean-Stark apparatus. The reaction mixture is partially concentratedunder vacuum and is left to crystallize. The crystalline product formedis spin-filtered off and washed with iso ether. 40 g of the expectedproduct are obtained.

C) 5-Chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

40 g of the compound obtained in the preceding step are added rapidly to550 g of polyphosphoric acid and the mixture is then heated at 60° C.for 8 hours and left stirring overnight while allowing the temperatureto return to RT. Ice-cold water is added to the reaction mixture and theprecipitate formed is spin-filtered off and washed with water. Theprecipitate is taken up in EtOAc and the white product obtained afterslurrying is spin-filtered off and washed with iso ether. 17.2 g of theexpected product are obtained; m.p.=243-247° C.

D)5-Chloro-3-(2-chlorophenyl)-3-hydroxy-6-methoxy-1,3-dihydro-2H-indol-2-one

2.56 g of 60% sodium hydride in oil are added at RT, under an argonatmosphere, to a solution of 17.2 g of the compound obtained in thepreceding step in 220 ml of THF. After the evolution of gas has ceased,6.85 g of dimethyl disulphide are added, air is bubbled into thereaction mixture and this mixture is left stirring for 72 hours at RT.Water is added to the reaction mixture, the THF is evaporated off undervacuum, the remaining aqueous phase is extracted with EtOAc, the organicphase is washed with water and with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The productobtained is dissolved in DCM, the solvent is partially concentrated, themixture is left to crystallize and the crystalline product formed isspin-filtered off. 6 g of the expected product are obtained;m.p.=237-240° C.

E) 3,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

A suspension of 2.0 g of the compound obtained in the preceding step in30 ml of DCM is cooled on an ice bath, 0.5 ml of pyridine and then 0.44ml of thionyl chloride are added and this mixture is left stirring for30 minutes. At the end of the reaction, a solution of the expectedproduct is obtained, and this solution is used directly in Preparations3.37 and 3.38.

Preparation 1.213,5-Dichloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=4-OCH₃; R₃=2-Cl; R₄═H; Hal=Cl

A) 5-Chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one and5-chloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

The process is performed as in step C of Preparation 1.20. Afterspin-filtration of the precipitate formed corresponding to5-chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one, thespin-filtration liquor is concentrated under vacuum to give a mixture ofthe two expected products, which is used without further purification.

B)5-Chloro-3-(2-chlorophenyl)-3-hydroxy-4-methoxy-1,3-dihydro-2H-indol-2-one

1.14 g of 60% sodium hydride in oil are added at RT to a solution of 8 gof the mixture of compounds obtained in the preceding step in 100 ml ofTHF. After the evolution of gas has ceased, 3 ml of dimethyl disulphideare added, air is bubbled into the reaction mixture and this mixture isleft stirring for 72 hours at RT. Water is added to the reactionmixture, the solvents are concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. 3.05 g of the expected product are obtainedafter crystallization from DCM; m.p.=228-229° C.

C) 3,5-Dichloro-3-(2-chlorophenyl)-4-methoxy-1,3-dihydro-2H-indol-2-one

A suspension of 1.5 g of the compound obtained in the preceding step in20 ml of DCM is cooled on an ice bath, 0.37 ml of pyridine and then 0.34ml of thionyl chloride are added and the mixture is left stirring for 15minutes. At the end of the reaction, a solution of the expected productin DCM is obtained and is used in this form in Preparations 3.39 and3.40.

Preparation 1.223-Bromo-5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=7-F; R₃=2-Cl; R₄═H; Hal=Br

This compound is prepared according to the procedures disclosed in WO95/18105 in steps A, B and C of Preparation 73.

Preparation 1.233,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄═H; Hal=Cl

A) 6-Chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one

8.5 ml of chlorine are introduced into 320 ml of DCM cooled to −70° C.,followed by addition, over 20 minutes and at −70° C., of a solution of24 ml of ethyl methylthioacetate in 60 ml of DCM, and the mixture isleft stirring for 15 minutes at −70° C. A solution of 52.64 g of3-chloro-4-methylaniline in 100 ml of DCM is then added, at −70° C. andover 30 minutes, and the resulting mixture is left stirring for 1 hour45 minutes at −70° C. Finally, 41.3 ml of triethylamine are added at−70° C. and the mixture is left stirring for 1 hour while allowing thetemperature to rise to RT. The reaction mixture is washed twice with 250ml of water, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up in a mixture of 600ml of ether and 130 ml of 2N HCl and is left stirring for 72 hours atRT. An insoluble material is filtered off, the filtrate is allowed toseparate by settling, the organic phase is washed twice with water anddried over MgSO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/EtOAc mixture (85/15; v/v). The mixture obtained isre-chromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (95/5; v/v). The two isomers are separated:

-   -   the less polar isomer, which is        6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, in a        yield of 1.16 g;    -   the more polar isomer, which is        4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, in a        yield of 0.72 g.

B) 6-Chloro-5-methyl-1H-indole-2,3-dione

A mixture of 1.16 g of6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one obtained inthe preceding step and 0.681 g of N-chlorosuccinimide in 100 ml ofcarbon tetrachloride is refluxed for 1 hour. The reaction mixture isconcentrated under vacuum, the residue is taken up in a mixture of 80 mlof THF and 20 ml of water, and this mixture is then refluxed for 16hours. The THF is evaporated off under vacuum, the remaining aqueousphase is extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a gradient of a DCM/EtOAc mixture upto (85/15; v/v). 0.793 g of the expected product is obtained; m.p.=264°C.

C)6-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

A solution of 2-methoxyphenylmagnesium bromide is prepared starting with0.687 g of magnesium in 1.5 ml of ether and a solution of 5.35 g of1-bromo-2-methoxybenzene in 7.55 ml of ether. This solution is addeddropwise, under an argon atmosphere, to a mixture of 1.4 g of thecompound obtained in the preceding step in 14 ml of THF precooled on anice bath, and the resulting mixture is then left stirring while allowingthe temperature to rise to RT. After stirring for 1 hour at RT, thereaction mixture is poured slowly into saturated NH₄Cl solution, the THFis evaporated off under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with water and with saturated NaCl solution anddried over Na₂SO₄, and the EtOAc is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/MeOH mixture (98/2; v.v). 1.6 g of the expected product areobtained after crystallization from a THF/MeOH mixture; m.p.=266° C.

D) 3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

A suspension of 0.913 g of the compound obtained in the preceding stepin 10 ml of DCM is cooled on an ice bath, 0.36 ml of pyridine and then0.33 ml of thionyl chloride are added and the mixture is left stirringfor 20 minutes. The reaction mixture is diluted by adding 50 ml of DCM,the organic phase is washed three times with water and dried over Na₂SO₄and is partially concentrated under vacuum to a volume of 5 ml. Thissolution of the expected product is used in this form in Preparations3.43 and 3.44.

Preparation 1.243,4-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═CH₃; R₂=4-Cl; R₃=2-OCH₃; R₄═H; Hal=Cl

A) 4-Chloro-5-methyl-1H-indole-2,3-dione

This compound is prepared according to the procedure described in step Bof Preparation 1.23, starting with 0.72 g of4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and 0.422 g ofN-chlorosuccinimide in 72 ml of carbon tetrachloride, and then 58 ml ofTHF and 14 ml of water. The product obtained is chromatographed onsilica gel, eluting with DCM and then with a gradient of a DCM/EtOAcmixture up to (90/10; v/v). 0.5 g of the expected product is obtained.

B)4-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

A solution of 5 g of 1-bromo-2-methoxybenzene in 7 ml of ether is addeddropwise to a suspension of 0.638 g of magnesium in 1.5 ml of etheruntil the reaction starts, and the addition is then continued whilemaintaining the reflux. At the end of the addition, the mixture isheated at 30° C. for 20 minutes. This solution is added dropwise, underan argon atmosphere, to a suspension of 1.3 g of the compound obtainedin the preceding step in 13 ml of THF precooled on an ice bath, and themixture is then left stirring while allowing the temperature to rise toRT. After 1 hour at RT, the reaction mixture is poured into saturatedNH₄Cl solution, the THF is evaporated off under vacuum, the residue isextracted with EtOAc, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (98/2; v/v).0.846 g of the expected product is obtained after crystallization from aTHF/MeOH mixture; m.p.=262-263° C.

C) 3,4-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

A suspension of 0.8 g of the compound obtained in the preceding step in15 ml of DCM is cooled to 0° C., 0.32 ml of pyridine and then 0.295 mlof thionyl chloride are added and the mixture is left stirring for 45minutes. The reaction mixture is diluted by adding 15 ml of DCM, theorganic phase is washed three times with water and dried over MgSO₄, andthe solvent is evaporated off under vacuum. 0.51 g of the expectedproduct is obtained.

Preparation 1.253-Chloro-3-(2-methoxyphenyl)-3,5,6,7-tetrahydrocyclopenta[f]indol-2(1H)-one

(IV): R₁═R₂=5,6-CH₂CH₂CH₂—; R₃=2-OCH₃; R₄═H; Hal=Cl

A) N-(2,3-Dihydro-1H-inden-5-yl)-2-(hydroxyimino)acetamide

This compound is prepared according to the process described in OrganicSyntheses, 1925, V, 71-74. A solution of 16.5 ml of concentrated HCl in120 ml of water and a solution of 41.5 g of hydroxylamine hydrochloridein 70 ml of water are added to a mixture of 25 g of 5-aminoindane, 35 gof chloral hydrate and 22 g of Na₂SO₄ in 600 ml of water, and themixture is then refluxed for 30 minutes. After cooling the reactionmixture to RT, it is extracted with EtOAc, the organic phase is driedover Na₂SO₄ and the solvent is evaporated off under vacuum. The residueis taken up in a pentane/iso ether mixture and the precipitate formed isspin-filtered off. 23 g of the expected product are obtained.

B) 1,5,6,7-Tetrahydrocyclopenta[f]indole-2,3-dione

This compound is prepared according to the process described in OrganicSyntheses, 1925, V, 71-74. 23 g of the compound obtained in thepreceding step are added portionwise to 250 ml of concentrated sulphuricacid, the temperature of the reaction mixture rising to 60° C. At theend of the addition, the mixture is heated at 90° C. for 50 minutes.After cooling to RT, the reaction mixture is poured into 1 litre of ice,500 ml of EtOAc are added and the mixture is filtered through Celite®.After separation of the filtrate by settling, the organic phase is driedover Na₂SO₄ and the solvent is evaporated off under vacuum. The residueis taken up in iso ether and the crystalline product formed isspin-filtered off. 4.2 g of the expected product are obtained.

C)3-Hydroxy-3-(2-methoxyphenyl)-3,5,6,7-tetrahydrocyclopenta[f]indol-2(1H)-one

A solution of 2-methoxyphenylmangesium bromide is prepared starting with2.4 g of magnesium, 16.5 g of 1-bromo-2-methoxybenzene and 50 ml ofether. This solution is added dropwise, at a temperature below 30° C.,to a mixture of 6.3 g of the compound obtained in the preceding step in50 ml of THF, and the resulting mixture is then refluxed for 2 hours.After cooling to RT, the reaction mixture is poured into a 3N HCl/icemixture and extracted with EtOAc, the organic phase is washed with waterand dried over Na₂SO₄, and the solvent is evaporated off under vacuum.The residue is taken up in hot iso ether and the precipitate formed isspin-filtered off and washed with boiling iso ether. 3.5 g of theexpected product are obtained.

D)3-Chloro-3-(2-methoxyphenyl)-3,5,6,7-tetrahydrocyclopenta[f]indol-2(1H)-one

A mixture of 3.5 g of the compound obtained in the preceding step and 1ml of triethylamine in 20 ml of DCM is cooled to 10° C., 0.8 ml ofthionyl chloride is added and the mixture is left stirring for 15minutes. The reaction mixture is washed with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The expectedproduct is obtained and is used without further purification.

Preparation 1.263-Chloro-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═CH₃; R₂=6-CH₃; R₃=2-OCH₃; R₄=6-CH₃; Hal=Cl

A) 5,6-Dimethyl-1H-indol-2,3-dione

This compound is prepared according to the procedures described in stepsA and B of Preparation 1.25, starting with 3,4-dimethylaniline.

B)3-Hydroxy-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

A solution of 2-methoxy-6-methylphenyl-magnesium bromide is preparedstarting with 13.75 g of 1-bromo-2-methoxy-6-methylbenzene, 1.9 g ofmagnesium and 30 ml of THF. This solution is added dropwise at RT to asuspension of 5 g of the compound obtained in the preceding step in 40ml of THF, and the resulting mixture is then refluxed for 1 hour 30minutes. After cooling to RT, 200 ml of 3N HCl solution are added, themixture is extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/EtOAc/THF mixture (70/20/10; v/v/v). 3 g of theexpected product are obtained after crystallization; m.p.=288° C.

C)3-Chloro-3-(2-methoxy-6-methylphenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

A mixture of 1.5 g of the compound obtained in the preceding step in 20ml of DCM is cooled on an ice bath, 0.4 ml of pyridine and then 0.5 mlof thionyl chloride are added and the mixture is left stirring for 15minutes under cold conditions and then for 15 minutes at RT. Asuspension of the expected product in DCM is obtained and is used inthis form in Preparation 3.47.

Preparation 1.273,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═Cl; R₂=6-CF₃; R₃=2-OCH₃; R₄═H; Hal=Cl

A)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-onea) tert-Butyl 4-chloro-3-trifluoromethyl-phenylcarbamate

This compound is prepared according to the procedure described in step Ba) of Preparation 1.5, starting with 4-chloro-3-trifluoromethylanilineand di-tert-butyl dicarbonate in dioxane. The expected product isobtained in the form of an oil which solidifies; m.p.=90° C.

b) A solution of 4 g of tert-butyl4-chloro-3-trifluoromethylphenylcarbamate in 30 ml of ether is cooled to−70° C., under an argon atmosphere, 22 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise and the mixture is leftstirring for 1 hour while allowing the temperature to rise to −10° C.and is left stirring for 2 hours 30 minutes at −10° C. The reactionmixture is cooled to −70° C., a solution of 3.05 g of the compoundobtained in step A of Preparation 1.19 in 15 ml of THF is added dropwiseand the resulting mixture is left stirring for 1 hour while allowing thetemperature to rise to −30° C., and is then stirred for 16 hours whileallowing the temperature to rise to RT. Saturated NH₄Cl solution isadded to the reaction mixture, the ether and THF are evaporated off, theresulting aqueous phase is extracted with EtOAc, the organic phase iswashed with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (90/10; v/v). 1.48 g of the expected product areobtained after crystallization from an iso ether/hexane mixture; m.p.230-231° C.

B)3,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

A suspension of 1.3 g of the compound obtained in step A in 8 ml of DCMis cooled to 0° C., 0.43 ml of pyridine and then 0.4 ml of thionylchloride are added and the mixture is left stirring for 15 minutes. Thereaction mixture is washed three times with water, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. 1.2 gof the expected product are obtained and are used without furtherpurification.

Preparation 1.283-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

(IV): R₁═CH₃; R₂=6-CH₃; R₃═Cl; R₄═H; Hal=Cl

A) N-(3,4-Dimethylphenyl)-D,L-2-chloromandelamide

A mixture of 50 g of 3,4-dimethylaniline and 76.5 g ofD,L-2-chloromandelic acid in 250 ml of 1,2-dichlorobenzene is heated at227° C. for 7 hours, while removing the water formed using Dean-Starkapparatus. The reaction mixture is concentrated to half its volume undervacuum and is left to crystallize at RT. The crystalline product formedis spin-filtered off and washed with iso ether. 89.42 g of the expectedproduct are obtained, a sample of which is recrystallized from a DCM/isoether mixture; m.p.=172-173° C.

B) 3-(2-Chlorophenyl)-5,6-dimethyl-1,3-dihydro-indol-2-one

100 ml of 95% sulphuric acid are cooled to −10° C., 12 ml of fumingsulphuric acid (65% oleum) are added dropwise over 30 minutes and themixture is left stirring while allowing the temperature to rise to +10°C. The mixture is cooled again to 0° C., 23.8 g of the compound obtainedin the preceding step are added portionwise over 10 minutes and themixture is left stirring while allowing the temperature to rise, whichstabilizes at 29° C. After stirring for 2 hours at RT, the reactionmixture is poured onto ice and the precipitate formed is spin-filteredoff. The precipitate is dissolved in 1 000 ml of DCM and 200 ml of THF,the pH is brought to 2 by adding solid K₂CO₃, the resulting mixture isfiltered and the filtrate is concentrated under vacuum. The residue ischromatographed on silica gel, eluting with a gradient of aDCM/EtOAc/THF mixture of from (90/10/5; v/v/v) to 80/20/5; v/v/v). 7.72g of the expected product are obtained; m.p.=231° C.

C) 3-(2-Chlorophenyl)-3-hydroxy-5,6-dimethyl-1,3-dihydroindol-2-one

0.65 g of 60% sodium hydride in oil is added at RT, under an argonatmosphere, to a solution of 4 g of the compound obtained in thepreceding step in 70 ml of THF. After the evolution of gas has ceased,1.7 ml of dimethyl disulphide are then added and a stream of air isbubbled into the reaction mixture for 4 hours at RT. The reactionmixture is poured into water, the THF is concentrated under vacuum, theaqueous phase is extracted with EtOAc, the organic phase is washed withwater and with saturated NaCl solution and dried over Na₂SO₄, thesolvent is partially concentrated under vacuum and the crystallineproduct formed is spin-filtered off. 3.3 g of the expected product isobtained; m.p.=251-253° C.

D) 3-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

A suspension of 2 g of the compound obtained in the preceding step in 15ml of DCM is cooled to 0° C., 0.8 ml of pyridine and then 0.74 ml ofthionyl chloride are added and the mixture is left stirring for 30minutes. The reaction mixture is diluted by adding 60 ml of DCM, theorganic phase is washed with 45 ml of water and dried over Na₂SO₄, andthe solvent is partially concentrated under vacuum at a temperaturebelow 40° C., to a volume of 20 ml. This solution is used in this formin Preparations 3.60 and 3.61.

Preparation of the compounds of formula (V)

Preparation 2.1 (2S)—N,N-Dimethylpyrrolidine-2-carbothioamidetrifluoroacetate

(V), TFA: R₅═N(CH₃)₂; W═S; n=1

A)(2S)-N,N-Dimethyl-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbothioamide

This compound is prepared according to the procedure described in stepA) of Example 84 of EP 0 526 348 B.

B) (2S)-N,N-Dimethylpyrrolidine-2-carbothioamide trifluoroacetate

A solution of 18 g of the compound obtained in the preceding step in 5ml of DCM is cooled to 4° C., 15 ml of TFA are added and the mixture isleft stirring for 15 hours at 4° C. The reaction mixture is concentratedunder vacuum under cold conditions, the residue is taken up four timesin DCM and the solvent is evaporated off under vacuum each time. 12 g ofthe expected product are obtained after drying, and are used withoutfurther purification.

Preparation 2.2 (2S)-N,N-Dimethylpiperidine-2-carboxamide hydrochloride

(V), HCl: R₅═N(CH₃)₂; W═O; n=2

A) (2S)-N,N-Dimethyl-2-(tert-butoxycarbonyl)-piperidine-2-carboxamide

6.2 g of HOBT and then 9.45 g of DCC are added at RT to a solution of 10g of (2S)-1-(tertbutoxycarbonyl)piperidine-2-carboxylic acid(commercial) in 130 ml of DCM, and the mixture is left stirring for 1hour. The reaction mixture is cooled on an ice bath, dimethylamine gasis added by bubbling for two times 10 minutes and the mixture is thenleft stirring overnight at RT. An insoluble material is filtered off andthe filtrate is concentrated under vacuum. The residue ischromatographed on silica gel, eluting with a gradient of a DCM/MeOHmixture of from (98/2; v/v) to (96/4; v/v). The product obtained istaken up in ether and the precipitate is spin-filtered off. 8.5 g of theexpected product are obtained.

B) (2S)—N,N-Dimethylpiperidine-2-carboxamide hydrochloride

A mixture of 8.5 g of the compound obtained in the preceding step and 85ml of 4N hydrochloric ether is left stirring for 1 hour 30 minutes. Thereaction mixture is concentrated under vacuum, the residue is taken upseveral times with DCM and the solvent is evaporated off each time undervacuum. 6.25 g of the expected product are obtained.

Preparation 2.3 N,N-Dimethylpiperidine-2-carboxamide hydrochloride

(V) , HCl: R₅═N(CH₃)₂; W═O; n=2

This compound is prepared according to the procedures described in stepsA and B of Preparation 2.2, starting with racemic1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid (commercial).

Preparation of the compounds of formulae (II) and (II′)

Preparation 3.1(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; n=1; W═O

4.1 g of (2S)—N,N-dimethylpyrrolidine-2-carboxamide (commercial) areadded to a suspension of 8.8 g of the compound obtained in Preparation1.1 in 120 ml of chloroform and 30 ml of THF, and the mixture is leftstirring for 30 minutes at RT. 3.7 g of DIPEA are then added and themixture is left stirring for 3 hours at RT. 0.4 g of(2S)—N,N-dimethylpyrrolidine-2-carboxamide is then added and the mixtureis left stirring for 48 hours. The reaction mixture is concentratedunder vacuum at RT, the residue is taken up in water, 300 ml of EtOAcare added, the mixture is left stirring and the precipitate present (themost polar compound on TLC on alumina DCM/MeOH (96/4; v/v)) isspin-filtered off. The precipitate is taken up in 100 ml of EtOAc, leftstirring for 2 hours and spin-filtered off. It is taken up in 100 ml ofboiling EtOAc, left stirring for 1 hour and spin-filtered off. Theprecipitate is dissolved in a hot mixture of 100 ml of THF, 50 ml ofMeOH and 10 ml of water, the resulting solution is filtered and thefiltrate is concentrated under vacuum to a volume of 100 ml and is leftovernight. 3.78 g of the expected product are obtained after thecrystalline compound formed has been spin-filtered off.

α_(D) ²⁵=−242° (c=0.12; chloroform)

Preparation 3.2 tert-Butyl(2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,laevorotatory isomer

(II′): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; n=1

A solution of 3.4 g of tert-butyl (2S)-pyrrolidine-2-carboxylate(commercial) in 5 ml of DCM is added to a suspension of 6 g of thecompound obtained in Preparation 1.1 in 40 ml of DCM and 20 ml of THF,followed by addition of 5.42 ml of triethylamine, and the mixture isleft stirring for 2 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is extracted with EtOAc, the organic phase iswashed with 5% K₂CO₃ solution, with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with DCMand then with a DCM/MeOH mixture (98/2 v/v). The diastereoisomers areseparated and the most polar compound is collected. 3.3 g of theexpected product are obtained.

α_(D) ²⁵=−148.5° (c=0.229; chloroform)

Preparation 3.3(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-2-yl]-N,N-dimethylpyrrolidine-2-carbothioamide,laevorotatory isomer

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═S

A solution of 3.5 g of the compound obtained in Preparation 2.1 and 3.5g of triethylamine in 20 ml of DCM is added dropwise at RT to a mixtureof 4 g of the compound obtained in Preparation 1.1 in 20 ml of DCM, andthe mixture is left stirring for 30 minutes at RT. A further 0.87 g oftriethylamine is added and the mixture is left stirring for 24 hours atRT. The resulting mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% KHSO₄ solutionand with water and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (99.75/0.25; v/v). The diastereoisomers are separatedto give 0.7 g of the expected product after crystallization from aDCM/iso ether mixture; m.p.=225° C.

α_(D) ²⁵=−236° (c=0.2; chloroform)

Preparation 3.4 Methyl(2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate;the more Polar Isomer

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═OCH₃; n=1; W═O.

A solution of 1.7 g of methyl (2S)-pyrrolidine-2-carboxylatehydrochloride (commercial) and 1.73 ml of DIPEA in 50 ml of DCM is addedat RT to a suspension of 3 g of the compound obtained in Preparation 1.1in 20 ml of THF, and the mixture is heated at 65° C. overnight. Thereaction mixture is concentrated under vacuum, the residue is taken upin 5% K₂CO₃ solution and extracted with EtOAc, the organic phase iswashed with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/EtOAc mixture (95/5; v/v). Thediastereoisomers are separated and the fractions enriched in the morepolar compound are collected. 0.793 g of the expected product isobtained and is used without further purification.

Preparations 3.5 and 3.6(2S)-1-[5-Chloro-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₂CH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 2.5 g of the compound obtained in Preparation 1.2, 1.2[lacuna] of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml oftriethylamine in 20 ml of DCM is left stirring for 3 hours. The reactionmixture is washed twice with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue istaken up in DCM under cold conditions over 16 hours and the precipitateformed is spin-filtered off and washed with acetone to give 0.35 g ofthe less polar isomer, isomer A: compound of Preparation 3.5. Thespin-filtration and washing liquors are chromatographed on alumina,eluting with a DCM/MeOH mixture (98/2; v/v). The other isomer isseparated out:

-   -   the more polar isomer, isomer B: compound of Preparation 3.6, to        give 0.52 g.

Preparations 3.7 and 3.8(2S)-1-[5-Chloro-3-(3-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=3-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1 g of the compound obtained in Preparation 1.3, 0.7 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in20 ml of DCM is left stirring for 2 hours at RT. The reaction mixture iswashed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is taken up in DCM,cooled to 4° C. and left for 16 hours. The precipitate formed isspin-filtered off and dried to give 0.72 g of the more polar isomer,isomer B: compound of Preparation 3.8. The spin-filtration liquor ischromatographed on alumina, eluting with a DCM/MeOH mixture (99.9/0.1;v/v). The other isomer is separated out:

-   -   the less polar isomer, isomer A: compound of Preparation 3.7, to        give 0.18 g.

Preparations 3.9 and 3.10(2S)-1-[5-Chloro-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=4-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

1.1 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide are added at RT tothe solution of the compound obtained in Preparation 1.4 in DCM, themixture is left stirring for 15 minutes at RT, 1.2 g of triethylamine isthen added and this mixture is left stirring for 30 minutes at RT. Thereaction mixture is washed with water, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue istaken up in cold acetone and the crystalline product formed isspin-filtered off to give 0.75 g of the more polar isomer, isomer B:compound of Preparation 3.10. The spin-filtration liquor ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (95/5;v/v). The other isomer is separated out:

-   -   the less polar isomer, isomer A: compound of preparation 3.9, to        give 0.37 g.

Preparations 3.11 and 3.12(2S)-1-[5-Chloro-3-(2,3-diemthoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=3-OCH₃; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1 g of the compound obtained in Preparation 1.5, 0.5 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.3 g of triethylamine in5 ml of DCM and 15 ml of THF is left stirring for 16 hours at RT. Theprecipitate formed is spin-filtered off, washed with THF and dried togive 0.22 g of the less polar isomer, isomer A: compound of Preparation3.11. The spin-filtration and washing liquors are concentrated undervacuum and the residue is chromatographed on silica gel, eluting with aDCM/MeOH mixture (98.5/1.5; v/v). The other isomer is separated out:

-   -   the more polar isomer, isomer B: compound of Preparation 3.12,        to give 0.68 g.

Preparations 3.13 and 3.14(2S)-1-[5-Chloro-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=4-OCH₃; R₅═N(CH₃)₂; n=1; W═O

0.7 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.8 ml oftriethylamine are added at RT to the solution of the compound obtainedin Preparation 1.6. in DCM, and the mixture is left stirring for 1 hourat RT. The reaction mixture is washed twice with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (99.9/01.; v/v). The diasteroisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.13, to give        0.13 g.    -   the more polar, isomer B: compound of Preparation 3.14, to give        0.17 g.

Preparations 3.15 and 3.16(2S)-1-[5-Chloro-3-(2,5-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=5-OCH₃; R₅═N(CH₃)₂; n=1; W═O

[lacuna] Preparation 1.7, 0.5 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.3 g of triethylamine in10 ml of DCM [lacuna]. The reaction mixture is washed with 5% NaHCO₃solution and with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with DCM and then with a DCM/MeOH mixture (98/2;v/v). The diasteroisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.15, to give        0.2 g.    -   the more polar, isomer B: compound of Preparation 3.16, to give        0.38 g.

Preparations 3.17 and 3.18(2S)-1-[5-Chloro-3-(2,6-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=6-OCH₃; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1.9 g of the compound obtained in Preparation 1.8, 1 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in20 ml of DCM is left stirring for 3 hours at RT. The reaction mixture iswashed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (98/2; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.17, which is        crystallized from iso ether to give 0.38 g.

α_(D) ²⁵=−371° (c=0.15, chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.18, to give        0.4 g.

Preparations 3.19 and 3.20(2S)-1-[5-Chloro-3-(3,5-dimethoxyphenyl)-2-oxo-3,4-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=3-OCH₃; R₄=5-OCH₃; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1.4 g of the compound obtained in Preparation 1.9, 0.7 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.8 ml of triethylaminein 20 ml of DCM is left stirring for 3 hours at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/EtOAc mixture (95/5; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.19, to give        0.18 g.    -   the more polar, isomer B: compound of Preparation 3.20.

Preparations 3.21 and 3.22(2S)-1-[5-Chloro-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃+R₄=2,3-O—CH₂—O—; R₅═N(CH₃)₂; n=1; W═O

A mixture of 0.61 g of the compound obtained in Preparation 1.10, 0.45 gof (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylaminein 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (98.5/1.5; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.21, to give        0.19 g; m.p.=241° C.    -   the more polar, isomer B: compound of Preparation 3.22.

Preparations 3.23 and 3.24(2S)-1-[5-Chloro-3-(2-trifluoromethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,isomer A and isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCF₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1.8 g of the compound obtained in Preparation 1.11, 1.5 gof (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 2 ml of DIPEA in 20 mlof DCM is left stirring for 3 hours at RT. The reaction mixture iswashed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (99/1; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.23, to give        0.34 g.    -   the more polar, isomer B: compound of Preparation 3.24.

Preparations 3.25 and 3.26(2S)-1-[5-Chloro-3-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-F; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1.56 g of the compound obtained in Preparation 1.21, 1 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in50 ml of DCM is left stirring for 24 hours at RT. The precipitate formedis spin-filtered off and washed with DCM to give 0.62 g of the morepolar isomer, isomer B: compound of Preparation 3.26;

α_(D) ²⁰=+99° (c=0.15; chloroform).

The spin-filtration and washing liquors are concentrated under vacuum,the residue is taken up in a minimum amount of DCM, the precipitate ofisomer B formed is spin-filtered off again and the spin-filtrationliquor is concentrated under vacuum. The residue is chromatographed onalumina, eluting with a DCM/MeOH mixture (99.5/0.5; v/v). The otherisomer is separated out:

-   -   the less polar, isomer A: compound of        Preparation 3.25, to give 0.42 g.

α_(D) ²⁰=−182° (c=0.14; chloroform).

Preparation 3.27(2S)-1-[5-Chloro-3-(2-benzyloxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,laevorotatory isomer

(II): R₁═Cl; R₂═H; R₃=2-OBzl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 4 g of the compound obtained in Preparation 1.13, 1.8 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 3 ml of triethylamine in20 ml of DCM is left stirring for 12 hours at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is taken up in aTHF/iso ether mixture and left to crystallize. The precipitate formed isspin-filtered off to give 2.2 g of the more polar compound by TLC onalumina, DCM/MeOH (99/1; v/v). The spin-filtration liquor ischromatographed on alumina, eluting with a DCM/MeOH mixture (99/1; v/v)and a further 0.4 g of the more polar compound is collected. The 2.6 gof the more polar compound thus obtained are re-chromatographed onalumina, eluting with a DCM/MeOH mixture (99/1; v/v). 2.1 g of theexpected product are obtained; m.p.=240° C.

α_(D) ²⁰=−171° (c=0.15; chloroform).

Preparations 3.28 and 3.29(2S)-1-[5-Chloro-3-(2-methoxy-6-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=6-CH₃; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1 g of the compound obtained in Preparation 1.14, 0.5 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in20 ml of DCM is left stirring for 48 hours. The reaction mixture iswashed with water, with 5% NaHCO₃ solution and with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH mixture (98/2; v/v). The diastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.28, to give        0.4 g.    -   the more polar, isomer B: compound of Preparation 3.29, to give        0.6 g.

Preparation 3.30(2S)-1-(5-Trifluoromethoxy-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,the Less Polar Isomer

(II): R₁═OCF₃; R₂═H; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

0.839 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and 0.5 ml ofDIPEA are added to the solution of the compound obtained in Preparation1.15 in DCM and the mixture is then heated at 35° C. for 4 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upin 5% K₂CO₃ solution and extracted with EtOAc, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed three times successively on alumina, elutingwith a DCM/MeOH mixture (98/2; v/v). The diastereoisomers are separatedand the less polar compound is collected during the chromatography, butthe more polar compound is collected by TLC on alumina, eluting withDCM/MeOH (99.5/0.5; v/v). 0.371 g of the expected product is obtained.

Preparation 3.31(2S)-1-[5,6-Dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Mixture of Diastereoisomers

(II): R₁═Cl; R₂=6-Cl; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

0.81 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide is added to amixture of 1.95 g of the compound obtained in Preparation 1.16 in 25 mlof DCM, followed by addition of 2 ml of DIPEA, and the mixture is leftstirring overnight at RT. The reaction mixture is concentrated undervacuum, the residue is taken up in saturated K₂CO₃ solution andextracted three times with EtOAc, the organic phase is washed threetimes with water and with saturated NaCl solution and dried over Na₂SO₄,and the solvent is evaporated off under vacuum. 1.774 g of the expectedproduct are obtained in the form of a mixture of diasteroisomers aftercrystallization from iso ether.

Preparation 3.32(2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Mixture of Diastereoisomers

(II): R₁═Cl; R₂=6-Cl; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 1 g of the compound obtained in Preparation 1.17 and 0.73 gof (2S)-N,N-dimethylpyrrolidine-2-carboxamide in 10 ml of chloroform isleft stirring for 48 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up in 5% K₂CO₃ solution and extractedwith EtOAc (presence of a precipitate in the organic phase), the organicphase is washed twice with water, the phases are separated by settlingand THF is added until the precipitate has dissolved. The solvents arepartially concentrated under vacuum to give a precipitate in the EtOAc;iso ether is added until precipitation is complete and the precipitateformed is spin-filtered off. 1 g of the expected product is obtained inthe form of the mixture of diastereoisomers.

Preparations 3.33 and 3.34(2S)-1-[4,5-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=4-Cl; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A solution of 1.5 g of the compound obtained in Preparation 1.18 in 15ml of DCM is cooled on an ice bath, 1.09 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide are added and the mixture isleft stirring for 3 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up in water and extracted with EtOAc,the organic phase is washed with 5% K₂CO₃ solution, with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on alumina,eluting with DCM and then with a DCM/MeOH mixture (98/2; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.33, which is        crystallized under cold conditions from DCM to give 0.487 g.

α_(D) ²⁵=+243.7° (c=0.2; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.34, to give        0.3 g.

Preparations 3.35 and 3.36(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=6-CH₃; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O.

0.95 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then 0.66 g oftriethylamine are added at RT to a solution of the compound obtained inPreparation 1.19 in 20 ml of DCM, and the mixture is left stirring for 5minutes at RT. The reaction mixture is poured into 5% K₂CO₃ solution andextracted with EtOAc, and the precipitate formed is spin-filtered off.The precipitate is dissolved in hot THF and the solution is filtered andcombined with the EtOAc organic phase. The solvents are partiallyconcentrated under vacuum and the crystalline product formed isspin-filtered off [lacuna], the more polar isomer, by TTC on alumina,eluting with DCM/MeOH 98/2; v/v), isomer B: compound of Preparation3.36. Isomer B is recrystallized three times from a DCM/EtOAc mixtureand is then chromatographed on alumina, eluting with a DCM/MeOH mixture(99.5/0.5; v/v). 0.779 g of isomer B is obtained after crystallizationfrom a DCM/iso ether mixture; m.p.=266-269° C.

α_(D) ²⁵=−234.5° (c=0.18; chloroform)

The spin-filtration liquors from all the above crystallizations arecombined and concentrated under vacuum. The residue is chromatographedon alumina, eluting with a DCM/MeOH mixture (99.5/0.5; v/v) and theother diastereoisomer is separated out:

-   -   the less polar, isomer A: compound of Preparation 3.35, which is        crystallized from a DCM/EtOAc mixture to give 0.47 g;        m.p.=257-260° C.

α_(D) ²⁵=+122.1° (c=0.26; chloroform)

Preparations 3.37 and 3.38(2S)-1-[5-Chloro-3-(2-chlorophenyl)-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=6-OCH₃; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

The solution of the compound obtained in Preparation 1.20 in DCM iscooled on an ice bath, 1.75 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide are added and the mixture isleft stirring for 3 hours while allowing the temperature to return toRT. The reaction mixture is concentrated under vacuum, the residue istaken up in 5% K₂CO₃ solution and extracted with EtOAc containing THFand MeOH, the organic phase is washed with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (99/1; v/v) and then (98/2; v/v). The diastereoisomersare separated:

-   -   the less polar, isomer A: compound of Preparation 3.37, which is        crystallized from a DCM/iso ether mixture to give 0.51 g;        m.p.=240-247° C.

α_(D) ²⁵=+190.7° (c=0.16; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.38, which is        crystallized from a DCM/MeOH mixture to give 0.664 g; m.p.        239-244° C.

α_(D) ²⁵=−289.8° (c=0.15; chloroform/MeOH 7/1)

Preparations 3.39 and 3.40(2S)-1-[5-Chloro-3-(2-chlorophenyl)-4-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=4-OCH₃; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

1.31 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then 1.2 g ofDIPEA are added at RT to the solution of the compound obtained inPreparation 1.21 in DCM. The reaction mixture is concentrated undervacuum, the residue is extracted with EtOAc, the organic phase is washedwith 5% K₂CO₃ solution, with water and with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina, eluting with a DCM/MeOH mixtureof from (97.5/2.5; v/v) to (97/3; v/v). The diastereoisomers areseparated:

-   -   the less polar, isomer A: compound of Preparation 3.39, which is        crystallized from a DCM/iso ether mixture to give 0.42 g;        m.p.=259-260° C.

α_(D) ²⁵=+206.9° (c=0.13; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.40, to give        0.32 g.

Preparations 3.41 and 3.42(2S)-1-[5-Chloro-3-(2-chlorophenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=7-F; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A solution of 1.45 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide in 5ml of DCM is added dropwise at RT to a solution of 1.9 g of the compoundobtained in Preparation 1.22 in 15 ml of THF, and the mixture is leftstirring for 12 hours at RT. Water is added to the reaction mixture, theTHF and DCM are evaporated off under vacuum, the resulting aqueous phaseis extracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with DCM and then with a DCM/MeOHmixture (98.5/1.5; v/v). The diastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.41, which is        crystallized from a DCM/iso ether/hexane mixture to give 0.612        g; m.p.=246-247° C.

α_(D) ²⁵=+194.4° (c=0.2; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.42, to give        0.61 g.

Preparations 3.43 and 3.44(2S)-1-[6-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

0.855 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide is added at RT tothe solution of the compound obtained in Preparation 1.23 in DCM, andthe mixture is left stirring overnight at RT. The reaction mixture isconcentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with 5% K₂CO₃ solution and dried over Na₂SO₄,and the solvent is partially concentrated under vacuum. The crystallineproduct formed is spin-filtered off [lacuna], the more polar isomer, byTLC on alumina, eluting with EtOAc, isomer B: compound of Preparation3.44. 0.32 g of isomer B is obtained after recrystallization from aDCM/EtOAc mixture; m.p.=263° C.

α_(D) ²⁵=−256.8° (c=0.17; chloroform)

The above crystallization spin-filtration liquors are concentrated undervacuum and the residue is chromatographed on alumina, eluting with aDCM/MeOH mixture of from (99.75/0.25; v/v) to (98.5/1.5; v/v). The otherdiastereoisomer is separated out:

-   -   the less polar, isomer A: compound of Preparation 3.43, which is        crystallized from a DCM/iso ether/hexane mixture; m.p.=257° C.

α_(D) ²⁵=+131° (c=0.18; chloroform)

Preparation 3.45(2S)-1-[4-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Diastereoisomer Mixture

(II): R₁═CH₃; R₂=4-Cl; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of 0.503 g of the compound obtained in Preparation 1.24 and0.476 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide in 5 ml of DCM isleft stirring for 18 hours at RT. The reaction mixture is diluted byadding 30 ml of DCM, the organic phase is washed with water and driedover Na₂SO4, and the solvent is evaporated off under vacuum. The residueis chromatographed on silica gel, eluting with a DCM/MeOH mixture (96/4;v/v). 0.369 g of the expected product is obtained in the form of amixture of diastereoisomers.

Preparation 3.46(2S)-1-[3-(2-Methoxyphenyl)-2-oxo-1,2,3,5,6,7-hexahydrocyclopenta[f]indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Diastereoisomer Mixture

(II): R₁+R₂=5,6-CH₂CH₂CH₂—; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A mixture of the compound obtained in Preparation 1.25, 1 g of(2S)-N,N-dimethylpyrrolidine-2-carboxamide and 1 ml of triethylamine in30 ml of DCM is left stirring for 48 hours at RT. The reaction mixtureis washed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/EtOAc mixture (90/10; v/v). 0.87 g ofthe expected product is obtained after crystallization from a DCM/isoether mixture.

Preparation 3.47(2S)-1-[3-(2-Methoxy-6-methylphenyl)-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,the More Polar Isomer

(II): R₁═CH₃; R₂=6-CH₃; R₃=2-OCH₃; R₄=6-CH₃; R₅═N(CH₃)₂; n=1; W═O

1.43 g of (2S)-N,N-dimethylpyrrolidine-2-carboxamide and then 1.75 ml ofDIPEA are added at RT to the suspension of the compound obtained inPreparation 1.26 in DCM, and the mixture is left stirring overnight. Thereaction mixture is concentrated under vacuum, the residue is taken upin 5% K₂CO₃ solution and extracted with EtOAc, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOHmixture (96/4; v/v) and the more polar compound is collected. 0.127 g ofthe expected product is obtained after crystallization from a DCM/isoether mixture; m.p.=194-197° C.

Preparations 3.48 and 3.49(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=1; W═O

A solution of 2.41 g of the compound obtained in Preparation 2.2 and 4ml of triethylamine in 10 ml of MeOH is added dropwise at RT to asuspension of 1.93 g of the compound obtained in Preparation 1.1 in 19ml of THF, and the mixture is left stirring for 12 hours at RT. Themixture is concentrated under vacuum, the residue is extracted withEtOAc, the organic phase is washed with 5% K₂CO₃ solution, with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (97/3; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.48, which is        re-chromatographed on alumina, eluting with DCM and then with a        DCM/MeOH mixture (97/3; v/v) to give 0.634 g after        crystallization from a DCM/iso ether mixture;

m.p.=229° C.

α_(D) ²⁵=+190.9° (c=0.188; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.49, which is        re-chromatographed on alumina, eluting with DCM and then with a        DCM/MeOH mixture (97/3; v/v) to give 0.987 g after        crystallization from a DCM/iso ether mixture;

m.p.=243° C.

α_(D) ²⁵=−182.7° (c=0.214; chloroform)

Preparations 3.50 and 3.511-[5-Chloro-3-(2,5-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Racemic Isomer A and Racemic Isomer B

(II): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=5-OCH₃; R₅═N(CH₃)₂; n=2; W═O

A solution of 2.13 g of the compound obtained in Preparation 1.7 in 14ml of DCM is cooled on an ice bath, 2.54 g of the compound obtained inPreparation 2.3 are added, followed by addition of 1.83 ml oftriethylamine, and the mixture is left stirring for 72 hours at RT.Water is added to the reaction mixture, the DCM is evaporated off undervacuum, the aqueous phase is extracted with EtOAc, the organic phase iswashed with 5% K₂CO₃ solution, with water and with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on alumina, eluting with DCM andthen with a DCM/MeOH mixture (99/1; v/v). The two pairs of enantiomersare separated:

-   -   the less polar, racemic isomer A: compound of Preparation 3.50,        which is crystallized from a DCM/iso ether/hexane mixture to        give 0.606 g,; m.p.=217° C.    -   the more polar, racemic isomer B: compound of Preparation 3.51.

Preparation 3.52(2S)-1-[5,6-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Mixture of Diastereoisomers

(II): R₁═Cl; R₂=6-Cl; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=2; W═O

2.66 ml of DIPEA are added to a mixture of 1.5 g of the compoundobtained in Preparation 2.2 in 20 ml of DCM, followed by addition of 3 gof the compound obtained in Preparation 1.17, and the mixture is leftstirring for 10 minutes at RT. The reaction mixture is washed with 5%K₂CO₃ solution and with saturated NaCl solution, the organic phase isdried over Na₂SO₄ and the solvents are concentrated under vacuum. Theresidue is chromatographed on alumina, eluting with a DCM/MeOH mixture(97.5/2.5; v/v). 1.821 g of the expected product are obtained.

Preparation 3.53(2S)-1-[5,6-Dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,the More Polar Isomer

(II): R₁═Cl; R₂=6-Cl; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=2; W═O

1.1 g of the compound obtained in Preparation 2.2 are added to a mixtureof 1.95 g of the compound obtained in Preparation 1.16 in 25 ml of DCM,followed by addition of 2 ml of DIPEA, and the mixture is left stirringovernight at RT. The mixture is concentrated under vacuum, the residueis taken up in 5% K₂CO₃ solution and extracted three times with EtOAc,the organic phase is washed with water and with saturated NaCl solutionand dried over Na₂SO₄, and the solvent is evaporated off under vacuum.The residue is chromatographed on alumina, eluting with DCM/MeOH (98/2;v/v). The diastereoisomers are separated and the more polar compound iscollected. 0.821 g of the expected product is obtained.

Preparations 3.54 and 3.55(2S)-1-[5-Chloro-3-(2-chlorophenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=7-F; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=2; W═O

1.6 g of the compound obtained in Preparation 2.2 are added to asolution of 3.4 g of the compound obtained in Preparation 1.22 in 30 mlof DCM, followed by addition of 4 ml of DIPEA, and the mixture is heatedat 40° C. for 4 hours. The mixture is concentrated under vacuum, theresidue is extracted with EtOAc and washed with 5% K₂CO₃ solution, withwater and with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with DCM/EtOAc (83/17; v/v) and thenre-chromatographed on alumina, eluting with a gradient of a DCM/MeOHmixture of from (99.25/0.75; v/v) to (96.5/3.5; v/v). Thediasteroisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.54, which is        crystallized from ether/hexane to give 0.53 g; m.p.=136° C.

α_(D) ²⁵=+200° (c=0.1; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.55, which is        crystallized from iso ether to give 1.51 g; m.p.=233° C.

α_(D) ²⁵=−275.8° (c=0.12; chloroform)

Preparations 3.56 and 3.57(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=6-CH₃; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=2; W═O

A mixture of 1.97 g of the compound obtained in Preparation 1.19, 1.25 gof the compound obtained in Preparation 2.2 and 2.2 ml of DIPEA in 25 mlof DCM is left stirring overnight at RT. The mixture is concentratedunder vacuum, extracted with EtOAc, washed with 5% K₂CO₃ solution andwith water and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. The residue is chromatographed on alumina, eluting withDCM/MeOH (99/1; v/v). The diastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.56, to give        0.92 g; m.p.=228-229° C.

α_(D) ²⁵=+197.5° (c=0.125; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.57, to give        1.527 g.

Preparations 3.58 and 3.59(2S)-1-[5-Chloro-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Isomer A and Isomer B

(II): R₁═Cl; R₂=6-CF₃; R₃=2-OCH₃; R₄═H; R₅═N(CH₃)₂; n=2; W═O

0.5 g of the compound obtained in Preparation 2.2 and 0.9 ml oftriethylamine are added at RT to a solution of 1.2 g of the compoundobtained in Preparation 1.27 in 7 ml of DCM, and the mixture is leftstirring for 18 hours. Water is added to the reaction mixture, the DCMis evaporated off under vacuum, the aqueous phase is extracted withEtOAc, the organic phase is washed with 5% K₂CO₃ solution, with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed onalumina, eluting with a DCM/MeOH mixture (99/1; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Preparation 3.58, which is        crystallized from DCM/iso ether to give 0.611 g; m.p.=241-242°        C.

α_(D) ²⁵=+204.63° (c=0.216; chloroform)

-   -   the more polar, isomer B: compound of Preparation 3.59, to give        0.77 g.

Preparations 3.60 and 3.611-[3-(2-Chlorophenyl)-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Racemic Isomer A and Racemic Isomer B

(II): R₁═CH₃; R₂=6-CH₃; R₃=2-Cl; R₄═H; R₅═N(CH₃)₂; n=2; W═O

20 ml of DCM, 1.6 g of the compound obtained in Preparation 2.3 and 2.7g of DIPEA are added to the solution of the compound obtained inPreparation 1.28 and the mixture is then heated at 45° C. for 3 hours.The mixture is concentrated under vacuum, the residue is taken up in 5%K₂CO₃ solution and extracted with EtOAc, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture of from(99.5/0.5; v/v) to (98/2; v/v). The two pairs of enantiomers areseparated:

-   -   the less polar, racemic isomer A: compound of Preparation 3.60,        which is crystallized from DCM/iso ether to give 0.31 g;        m.p.=168-170° C.    -   the more polar, racemic isomer B: compound of Preparation 3.61,        which is crystallized from DCM/iso ether to give 1.03 g.

EXAMPLE 1(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃; n=1;W═O

A suspension of 3.76 g of the compound obtained in Preparation 3.1 in 35ml of DMF is cooled on an ice bath, 0.407 g of 60% sodium hydride in oilis added, under an argon atmosphere, and the mixture is warmed to RT andleft stirring until dissolved. The reaction mixture is cooled on an icebath, 2.35 g of 2,4-dimethoxybenzenesulphonyl chloride are added and themixture is left stirring for 3 hours 30 minutes at RT. 5% K₂CO₃ solutionis added, the mixture is extracted with EtOAc, the organic phase iswashed with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is dissolved in DCM,iso ether and hexane are added, the solvents are partially concentratedunder vacuum at RT and the precipitate formed is spin-filtered off. 3.8g of the expected product are obtained.

α_(D) ²⁵=−226.9° (c=0.2; chloroform)

¹H NMR: d₆-DMSO: δ (ppm): 1.0 to 1.7: 2mt: 4H; 1.9 to 3.7: mt+2bs: 8H;3.2: s: 3H; 3.7: s: 3H; 4.3: d: 1H; 6.6: mt: 2H; 6.8: mt: 3H; 7.1: t:1H; 7.3: dd: 1H; 7.5: d: 1H; 7.6: d: 1H; 7.8: d: 1H.

EXAMPLE 2(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—NHCH₂CH₃; R₆=2-OCH₃; R₇═OCH₃;n=1; W═O

A) tert-Butyl(2S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,Laevorotatory Isomer

A solution of 3.25 g of the compound obtained in Preparation 3.2 in 30ml of DMF is cooled on an ice bath, 0.323 g of 60% sodium hydride in oilis added, under an argon atmosphere, and the mixture is left stirringfor 20 minutes. 1.9 g of 2,4-dimethoxybenzene-sulphonyl chloride arethen added and the mixture is left stirring for 4 hours at RT. Water isadded to the reaction mixture, the resulting mixture is extracted withEtOAc, the organic phase is washed with 5% K₂CO₃ solution, with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/MeOH mixture (99/1; v/v). 3.37g of the expected product are obtained after crystallization from aDCM/iso ether mixture; m.p.=136° C.

α_(D) ²⁵=−190.25° (c=0.195; chloroform)

B)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylicAcid

A mixture of 1.8 g of the compound obtained in the preceding step in 20ml of a 4N solution of HCl in dioxane is left stirring overnight at RT.The mixture is concentrated under vacuum, the residue is taken up in DCMand the solvent is evaporated off under vacuum. 1.64 g of the expectedproduct are obtained and are used without further purification.

C)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

A mixture of 0.5 g of the compound obtained in the preceding step, 0.44g of PYBOP and 0.108 g of DIPEA in 5 ml of DCM and 1 ml of THF is leftstirring for 5 minutes at RT, followed by addition of 0.11 g of a 70%solution of ethylamine in water, and the mixture is left stirring for 2hours at RT. The mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water and with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture (99/1; v/v).0.315 g of the expected product is obtained after crystallization from aDCM/iso ether mixture.

α_(D) ²⁵=−151.8° (c=0.22; chloroform)

¹H NMR: d₆-DMSO: δ (ppm): 1.0: t: 3H; 1.2 to 1.5: mt: 4H; 2.0 and 2.6:q+t: 2H; 3.0: mt: 2H; 3.4: s: 3H; 3.6: s: 3H; 3.8: bs: 4H; 6.6: s+dd:2H; 6.8: 2d: 2H; 7.2: mt: 2H; 7.4: dd: 1H; 7.6: 3d+s: 4H.

EXAMPLE 3(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)pyrrolidine,Laevorotatory Isomer

(I) R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H;

R₆=2-OCH₃; R₇═OCH₃; n=1; W═O.

A mixture of 0.56 g of the compound obtained in step B of Example 2,0.496 g of PYBOP and 0.114 g of DIPEA in 5 ml of DCM and 1 ml of THF isleft stirring for 5 minutes at RT, followed by addition of 0.18 g ofazetidine hydrochloride and 0.22 g of DIPEA, and the mixture is leftstirring for 3 hours at RT. The mixture is concentrated under vacuum,the residue is taken up in 5% K₂CO₃ solution and extracted with EtOAc,the organic phase is washed three times with 0.5 N HCl solution and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v). 0.32 g of the expectedproduct is obtained after crystallization from an ether/iso ether/hexanemixture;

m.p.=161-166° C.

α_(D) ²⁵=−169.8° (c=0.19; chloroform)

EXAMPLE 4(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carbothioamide,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃; n=1;W═S

A mixture of 0.27 g of the compound obtained in Preparation 3.3 in 5 mlof DMF is cooled to 4° C., 0.026 g of 60% sodium hydride in oil isadded, under a nitrogen atmosphere, and the mixture is left stirring for15 minutes at 4° C. 0.139 g of 2,4-dimethoxybenzenesulphonyl chloride isthen added and the mixture is left stirring for 3 hours at RT. 50 ml ofwater are added to the reaction mixture, the resulting mixture isextracted with EtOAc, the organic phase is washed with 5% Na₂CO₃solution, with saturated NaCl solution and with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (97/3;v/v). 0.18 g of the expected product is obtained after crystallizationfrom a DCM/iso ether mixture; m.p.=164° C.

α_(D) ²⁵=−25° (c=0.2; chloroform)

¹H NMR: d₆-DMSO: δ (ppm): 1.3 to 2.2: 4mt: 4H; 2.4 and 3.0: 2mt: 2H;2.7: s: 3H; 3.2: s: 3H; 3.4: s: 3H; 3.7: s: 3H; 3.9: s: 3H; 4.9: dd: 1H;6.7: mt: 2H; 6.9: mt: 3H; 7.3: dt: 1H; 7.4: dd: 1H; 7.8; d: 1H; 7.9: d:1H; 8.0: d: 1H

EXAMPLE 5 Methyl(2S)-1-[5-chloro-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylate,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—OCH₃; R₆=2-OCH₃; R₇═OCH₃; n=1;W═O

A solution of 0.793 g of the compound obtained in Preparation 3.4 in 8ml of DMF is cooled to 0° C., 0.096 g of 60% sodium hydride in oil isadded, under an argon atmosphere, and the mixture is left stirring untilthe evolution of gas has ceased. 0.564 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isleft stirring for 3 hours at RT. The reaction mixture is poured intowater and extracted with EtOAc, the organic phase is washed with waterand with saturated NaCl solution and dried over Na₂SO₄, and the solventis evaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/EtOAc mixture (97/3; v/v). The fractionscontaining only the more polar compound are collected. 0.495 g of theexpected product is obtained after crystallization from a DCM/isoether/ether mixture; m.p.=178=180° C.

α_(D) ²⁵=−197.3° (c=0.19; chloroform)

EXAMPLE 6(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OCH₂CH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=1; W═O

0.11 g of 60% sodium hydride in oil is added portionwise at RT to amixture of 0.52 g of the compound obtained in Preparation 3.6 (isomer B)in 20 ml of THF, and the mixture is left stirring for 15 minutes at RT.0.29 g of 2,4-dimethoxybenzene-sulphonyl chloride is then added and themixture is left stirring for 1 hour at RT. The reaction mixture ispoured into 100 ml of water and extracted with EtOAc, the organic phaseis washed with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (99/1; v/v). 0.54 g of the expectedproduct is obtained after crystallization from iso ether; m.p.=145° C.

α_(D) ²⁵=−205° (c=0.15; chloroform)

EXAMPLE 7(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═Cl; R₂═H; R₃=2-OH; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃; n=1;W═O

A)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-benzyloxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

0.2 g of 60% sodium hydride in oil is added portionwise at RT to amixture of 2 g of the compound obtained in Preparation 3.27 in 50 ml ofTHF, and the mixture is left stirring for 15 minutes. 1.2 g of2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture isleft stirring for 30 minutes at RT. The reaction mixture is poured intowater and extracted with EtOAc, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (95/5;v/v). 2.25 g of the expected product are obtained after crystallizationfrom iso ether.

α_(D) ²⁰=−245° (c=0.14; chloroform)

B)(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

1.2 g of the compound obtained in the preceding step, 1 ml oftrifluoroacetic acid, 0.5 ml of thioanisole and 10 ml oftrifluoromethanesulphonic acid are mixed together at a temperature below5° C. and the mixture is left stirring while allowing the temperature toreturn to RT and is then stirred for 15 minutes at RT. The reactionmixture is poured into an ice/water mixture and extracted with EtOAc,the organic phase is washed with water, with 5% NaHCO₃ solution and withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v). 0.6 g of the expected product is obtained;m.p.=143° C.

α_(D) ²⁰=−94° (c=0.12; chloroform)

¹H NMR: d₆-DMSO: δ (ppm): 1.4 to 2.0: 2up: 4H; 2.4 and 3.0: up+2s: 7H;3.4 to 4.0: 2s: 7H; 4.5: mt: 1H; 6.8 to 7.4: up: 7H; 7.6: dd: 1H; 7.9 to8.1: 2d: 2H; 10.0: bs: 1H

EXAMPLE 8(2S)-1-[5-Trifluoromethoxy-1-[(2,4-dimethoxy-phenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═OCF₃; R₂═H; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=1; W═O

0.035 g of 60% sodium hydride in oil is added at RT, under an argonatmosphere, to a solution of 0.371 g of the compound obtained inPreparation 3.30 in 5 ml of DMF, and the mixture is left stirring for 15minutes. 0.208 g of 2,4-dimethoxybenzenesulphonyl chloride is then addedand the mixture is left stirring for 3 hours at RT. The reaction mixtureis poured into 5% K₂CO₃ solution and extracted with EtOAc, the organicphase is washed with saturated NaCl solution and dried over Na₂SO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (80/20;v/v). The residue is dissolved in a minimum amount of MeOH, thissolution is poured into water and the precipitate formed isspin-filtered off. 0.335 g of the expected product is obtained afterdrying.

α_(D) ²⁵=−239° (c=0.17; chloroform/MeOH, 8/2; v/v)

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.0: 2up: 2H; 2.1 to 2.8: 2s+up: 8H;3.4: s: 3H; 3.6: s: 3H; 3.9: s: 3H; 4.5: d: 1H; 6.7 to 7.0: 2up: 5H;7.2: dt: 1H; 7.4: dd: 1H; 7.7: dd: 1H; 7.9: d: 1H; 8.0: d: 1H

EXAMPLES 9 AND 10(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Isomer A and Isomer B

(I): R₁═Cl; R₂=6-Cl; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=1; W═O

A mixture of 1.769 g of the compound obtained in Preparation 3.31 in 17ml of DMF is cooled on an ice bath, 0.187 g of 60% sodium hydride in oilis added, under an argon atmosphere, and the mixture is left stirringfor 10 minutes. 1.058 g of 2,4-dimethoxy-benzenesulphonyl chloride arethen added and the mixture is left stirring for 3 hours at RT. Water isadded and the reaction mixture is extracted with EtOAc, the organicphase is washed with water and with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on alumina, eluting with a DCM/hexane mixture (90/10;v/v). The diastereoisomers are separated:

-   -   the less polar, isomer A: compound of Example 9, which is        crystallized from iso ether to give 0.308 g; m.p.=193-194° C.

α_(D) ²⁰=+128.1° (c=0.149 chloroform)

-   -   the more polar, isomer B: compound of Example 10, which is        crystallized from iso ether and DCM to give 0.821 g; m.p.        231-232° C.

α_(D) ²⁵=−95.7° (c=0.116; chloroform)

EXAMPLE 11(2S)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide,Laevorotatory Isomer

(I): R₁═CH₃; R₂=6-Cl; R₃=2-OCH₃; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=1; W═O

A suspension of 0.295 g of the compound obtained in Preparation 3.44(isomer B) in 3 ml of DMF is cooled to 0° C., 0.03 g of 60% sodiumhydride in oil is added, under an argon atmosphere, and the mixture isleft stirring for 10 minutes. 0.18 g of 2,4-dimethoxybenzenesulphonylchloride is then added and the mixture is left stirring for 3 hours atRT. Water is added and the reaction mixture is extracted with EtOAc, theorganic phase is washed with 5% K₂CO₃ solution, with water and withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM and then with a DCM/EtOAc mixture (98/2; v/v). Theproduct obtained is taken up in an iso ether/hexane mixture and theprecipitate formed is spin-filtered off. 0.193 g of the expected productis obtained; m.p.=204-206° C.

α_(D) ²⁵=−211.2° (c=0.11; chloroform)

-   -   ¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.2: up: 6H; 2.3: s: 3H; 2.4        and 2.8: 2s: 6H; 3.5: s: 3H; 3.8: s: 3H; 4.0: s: 3H; 4.5: d: 1H;        6.8 to 7.2: up: 5H; 7.3: dt: 1H; 7.7: dd: 1H; 7.8: s: 1H; 8.1:        d: 1H

EXAMPLE 121-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpyrrolidine-2-carboxamide

(I): R₁═Cl; R₂═H; R₃=2-OCH₃; R₄=5-OCH₃; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=2; W═O

This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.51(racemic isomer B). The product is chromatographed on silica gel,eluting with a DCM/MeOH mixture (98/2; v/v). The expected product isobtained after crystallization from a DCM/iso ether mixture;m.p.=212-214° C.

EXAMPLES 13 AND 14(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,Isomer A and Isomer B

(I): R₁═Cl; R₂=6-Cl; R₃=2-Cl; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=2; W═O

These compounds are prepared according to the procedure described inExamples 9 and 10, starting with 1.821 g of the compound obtained inPreparation 3.52. The product is chromatographed on alumina, elutingwith DCM and then with a DCM/MeOH mixture (95/5; v/v). Thediastereoisomers are separated:

-   -   the less polar, isomer A: compound of Example 13, which is        crystallized from DCM/heptane to give 0.824 g.

α_(D) ²⁵=+257.1° (c=0.105; chloroform)

-   -   the more polar, isomer B: compound of Example 14, which is        crystallized from iso ether to give 2.032 g; m.p.=257-258° C.

α_(D) ²⁵=−353.7° (c=0.108; chloroform)

EXAMPLE 151-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide

(I): R₁═CH₃; R₂=6-CH₃; R₃=2-Cl; R₄═H; R₅═—N(CH₃)₂; R₆=2-OCH₃; R₇═OCH₃;n=2; W═O

This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.61(racemic isomer B). The product is chromatographed on silica gel,eluting with a DCM/MeOH mixture (98/2; v/v). The expected product isobtained after crystallization from a DCM/iso ether mixture;m.p.=268-270° C.

Working according to the procedures described in the above examples,starting with the compounds of formula (II) described in Preparations 3and 2,4-dimethoxybenzenesulphonyl chloride, the compounds according tothe invention collated in Table I below are prepared. TABLE I (I)

m.p. ° C.; NMR crystallization Exam- solvent; ples n R₁ R₂ R₃ R₄ α_(D)²⁰ (chloroform) 16 1 Cl H 3-OCH₃ H — (a) — −87° (c = 0.15) 17 1 Cl H4-OCH₃ H — (b) — −238° (c = 0.14) 18 1 Cl H 2-OCH₃ 3-OCH₃ 178.5; NMR (c)iso ether −68° (c = 0.15) 19 1 Cl H 2-OCH₃ 4-OCH₃ 146; NMR (d) — −216°(c = 0.15) 20 1 Cl H 2-OCH₃ 5-OCH₃ — (e) — −266.7° (c = 0.15) 21 1 Cl H2-OCH₃ 6-OCH₃ 213 (f) — −303° (c = 0.13) 22 1 Cl H 3-OCH₃ 5-OCH₃ — (g) —−226° (c = 0.15) 23 1 Cl H 2,3- NMR (h) O—CH₂—O— — −81° (c = 0.14) 24 1Cl H 2-OCF₃ H — (i) — −218° (c = 0.14) 25 1 Cl H 2-F H 196 (j) iso ether−272° (c = 0.14) 26 1 Cl H 2-OCH₃ 6-CH₃ 193; NMR (k) iso ether −250° (c'2 0.15) 27 1 Cl 6-Cl 2-Cl H 288 (l) DCM/iso ether −328° (c = 0.23) 28 1Cl 4-Cl 2-Cl H 275-278 (m) DCM/isso ether −321° (c = 0.13) 29 1 Cl6-0CH₃ 2-OCH₃ H 207-210 (n) iso ether/hexane −191° (c = 0.16) 30 1 Cl6-OCH₃ 2-Cl H 278 (dec.); NMR (o) DCM/iso ether −318° (c = 0.16) 31 1 Cl4-OCH₃ 2-Cl H 212 (p) DCM/iso ether −269° (c = 0.117) 32 1 Cl 7-F 2-Cl H— (q) DCM/iso ether/hexane −206.8° (c = 0.1) 33 1 CH₃ 4-Cl 2-OCH₃ H NMR(r) DCM/iso ether/hexane −266° (c = 0.11) 34 1 5,6- 2-OCH₃ H 160 (s)CH₂CH₂CH₂— iso ether −174° (c = 0.15) 35 1 CH₃ 6-CH₃ 2-OCH₃ 6-CH₃ 235;NMR (t) DCM/iso ether — 36 2 Cl H 2-OCH₃ H 148-149; NMR (u) DCM/isoether −211° (c = 0.209) 37 2 Cl 6-Cl 2-OCH₃ H 239-2240; NMR (v) DCM/isoether −289.3° (c = 0.102) 38 2 Cl 7-F 2-Cl H 149-152 (w) DCM/iso ether−196.2° (c = 0.1) 39 2 Cl 6-CH₃ 2-OCH₃ H 236-237; NMR (x) DCM/iso ether−219.2° (c = 0.105) 40 2 Cl 6-CF₃ 2-OCH₃ H 229 (y) DCM/iso ether/hexane−209.47° (c = 0.243)(a) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.7(isomer A). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99.5/0.5; v/v).(b) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.9(isomer A). The product is chromatographed on silica gel, eluting withDCM.(c) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.12(isomer B). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v).(d) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.13(isomer A). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v).(e) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.15(isomer A). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v).(f) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.17(isomer A). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v).(g) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.19(isomer A). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99.5/0.5; v/v).(h) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.21(isomer A). The product is chromatographed on alumina, eluting with aDCM.(i) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.23(isomer A). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99.5/0.5; v/v).(j) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.25(isomer A). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v).(k) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.29(isomer B). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v).(l) This compound is prepared according to the procedure described inExamples 9 and 10, starting with the compound obtained in Preparation3.32. The product is chromatographed on alumina, eluting with aDCM/hexane mixture (90/10; v/v), the fractions enriched in the polarissomer are collected and this product is crystallized from a DCM/isoether mixture.(m) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.34(isomer B). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v).(n) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.36(isomer B). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (80/20; v/v).(o) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.38(isomer B). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (98/2; v/v).(p) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.40(isomer B). The product is chromatographed on alumina, eluting with aDCM/MeOH mixture (99.5/0.5; v/v) and then on silica, eluting with aDCM/MeOH mixture (98/2; v/v).(q) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.42(isomer B). The product is chromatographed on silica gel, eluting with aDCM and then with a DCM/MeOH mixture (98.5/1.5; v/v).(r) This compound is prepared according to the procedure described inExamples 9 and 10, starting with the compound obtained in Preparation3.45. The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (99/1; v/v) to (98/2; v/v) and is thenre-chromatographed on silica gel, eluting with a DCM/MeOH mixture (99/1;v/v) and the less polar compound is collected each time.(s) This compound is prepared according to the procedure described inExample 6, starting with the compound obtained in Preparation 3.46(isomer A). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v) and the less polar compound is collected,(t) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.47. Theproduct is chromatographed on silica gel, eluting with a DCM/MeOHmixture (98/2; v/v).(u) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.49(isomer B). The product is chromatographed on silica gel, eluting with aDCM and then with a DCM/EtOAc mixture (85/15; v/v).(v) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.53(isomer A). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (70/30; v/v).(w) This compound is prepared according to the procedure described inExample 8, starting with the compound obtained in Preparation 3.55(isomer B). The product is chromatographed on silica gel, eluting with aDCM/MeOH mixture (98/2; v/v).(x) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.57(isomer B). The product is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (70/30; v/v).(y) This compound is prepared according to the procedure described inExample 11, starting with the compound obtained in Preparation 3.59(isomer B). The product is chromatographed on silica gel, eluting with aDCM and then with a DCM/EtOAc mixture (90/10; v/v).

EXAMPLE 18

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: 2mt: 4H; 2.1 to 2.8: mt+3s: l1H;3.6 to 4.0: 3s: 9H; 4.5: mt: 1H; 6.6 to 7.2: mt: 5H; 7.3: t+dd: 1H; 7.4:mt: 1H; 7.9: dd+t: 1H; 8.1: d: 1H

EXAMPLE 19

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 2.0: 2mt: 4H; 2.2 to 2.8: mt+2s: 8H;3.5: s: 3H; 3.7: s: 3H; 3.8: s: 3H; 4.0: s: 3H; 4.6: d: 1H; 6.5: mt: 2H;6.8: mt: 2H; 7.0: d: 1H; 7.5: dd: 1H; 7.6: d: 1H; 7.9: d: 1H; 8.1: d: 1H

EXAMPLE 23

¹H NMR: d₆-DMSO: δ (ppm): 1.4 to 1.9: 2mt: 4H; 2.2 to 3.0: 2s+mt: 8H;3.4: s: 3H; 3.8: s: 3H; 4.4: dd: 1H; 5.3 and 5.6: 2s: 2H; 6.6 to 7.0:mt: 5H; 7.2: d: 1H; 7.4: dd: 1H; 7.9 to 8.0: 2d: 2H

EXAMPLE 26

¹H NMR: d₆-DMSO: δ (ppm): 1.1 to 1.8: m: 4H; 2.0: bs: 3H; 2.4: s: 3H;2.5 to 2.7: mt+3s: 5H; 3.3 to 3.9: 4s: 12H; 4.2 and 4.5: 2d: 1H; 6.6:mt: 4H; 7.0 to 7.2: mt: 2H; 7.3: 2dd: 1H; 7.6: 2d: 1H; 8.0: mt: 1H

EXAMPLE 30

¹H NMR: d₆-DMSO: δ (ppm): 1.3 to 1.9: 2mt: 4H; 2.2 to 3.0: up: 8H; 3.6:s: 3H; 3.9: s: 3H; 4.1: s: 3H; 4.5: t: 1H; 6.7: mt: 2H; 6.9: s: 1H; 7.3:up: 3H; 7.6: bs: 1H; 8.0: d: 2H

EXAMPLE 33

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.9: 2mt: 4H; 2.2: s: 3H; 2.5: s: 3H;2.5 to 3.6: 2bs: 8H; 3.7: s: 3H; 3.9: s: 3H; 4.5: d: 1H; 6.7: mt: 1H;6.8: mt: 1H; 7.2: dt: 1H; 7.4: d: 1H; 7.7: d: 1H; 7.8: d: 1H; 8.0: d: 1H

EXAMPLE 35

¹H NMR: d₆-DMSO: δ (ppm) : 1.0 to 2.0: 2up: 4H; 2.0 to 3.0: mt: 17H; 3.3to 3.9: 4s: 9H; 4.2 and 4.6: 2d: 1H; 6.6: up: 4H; 7.0: up: 2H; 7.6: s:1H; 8.0: mt: 1H

EXAMPLE 36

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: up: 6H; 2.2: bs: 2H; 2.5 to 2.8:2bs: 6H; 3.8: s: 3H; 3.9: bs: 4H; 6.7: mt: 4H; 7.0: t: 1H; 7.2: t: 1H;7.4: dd: 1H; 7.9: d: 1H; 8.0: d: 1H

EXAMPLE 37

¹H NMR: d₆-DMSO: δ (ppm): 1.1 to 2.0: up: 8H; 2.1 to 2.7: 2bs: 7H; 2.8:s: 3H; 3.8: s: 3H; 4.0: s: 3H; 6.8: mt: 3H; 6.9: s: 1H; 7.0: t: 1H; 7.2:t: 1H;, 7.8: d: 1H; 7.9 to 8.0: d+s: 2H

EXAMPLE 39

¹H NMR: d₆-DMSO: δ (ppm): 1.2 to 1.8: 2mt: 6H; 2.2: bs: 6H; 2.3: s: 3H;2.6: bs: 2H; 2.7: s: 3H; 3.8: s: 3H; 3.9: bs: 4H; 6.6: mt: 4H; 7.0: t:1H; 7.2: t: 1H; 7.7: s: 1H; 7.8: d: 1H; 8.0: d: 1H

1. A compound of formula (I):

in which: n is 2; W represents an oxygen atom or a sulphur atom; R₁represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; or a trifluoromethoxy radical; R₂ represents ahydrogen atom; a halogen atom; a C₁-C₄)alkyl; a C₁-C₄)alkoxy; or atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-onering and R₁ and R₂ together represent a trimethylene radical; R₃represents a halogen atom; a hydroxyl; a C₁-C₂)alkyl; a C₁-C₂)alkoxy; ora trifluoromethoxy radical; R₄ represents a hydrogen atom; a halogenatom; a C₁-C₂)alkyl; or a (C₁-C₂)alkoxy; or R₃ is in position -2- of thephenyl, R4 is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical; R₅ represents an ethylamino group; adimethylamino group; a 1-azetidinyl radical; or a (C₁-C₂)alkoxy; R₆represents a (C₁-C₄)alkoxy; and R₇ represents a (C₁-C₄)alkoxy; or asolvate or hydrate thereof.
 2. A compound according to claim 1, in theform of an optically pure isomers.
 3. A compound according to claim 2,of formula (Ia):

in which: the carbon atom bearing the substituent —C(W)R₅ has the (S)configuration and the carbon atom in position -3- of the indol-2-one haseither the (R) configuration or the (S) configuration.
 4. A compoundaccording to claim 3, in the form of the laevorotatory isomer.
 5. Acompound according to claim 1 in which: n is 2; W represents an oxygenatom; R₁ represents a chlorine atom or a methyl radical; R₂ represents ahydrogen atom or is in position -6- of the indol-2-one and represents achlorine atom, a methyl radical, a methoxy radical or a trifluoromethylradical; R₃ is in position -2- of the phenyl and represents a methoxyradical, a chlorine atom or a fluorine atom; R₄ represents a hydrogenatom, a methyl radical or a methoxy radical; or R₃ is in position -2- ofthe phenyl, R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical; R₅ represents a dimethylamino groupor a methoxy radical; R₆ is in position -2- of the phenyl and representsa methoxy radical; and R₇ represents a methoxy radical; or a solvate orhydrate thereof.
 6. A compound chosen from:(2S)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5,6-Dichloro-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer;(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide,laevorotatory isomer; and the solvates or hydrates thereof.
 7. A processfor preparing a compound according to claim 1, wherein: a compound offormula (II):

is reacted, in the presence of a base, with a halide of formula (III):

in which n, W, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in claim 1and Hal represents a halogen atom.
 8. A process for preparing a compoundaccording to claim 1, in which R₅ represents an ethylamino group, adimethylamino group or a 1-azetidinyl radical and W represents an oxygenatom wherein: a) a compound of formula (II′):

is reacted, in the presence of a base, with a halide of formula (III):

in which n, R₁, R₂, R₃, R₄, R₆ and R₇ are as defined in claim 1, to givea compound of formula (I′):

b) the compound of formula (I′) is hydrolysed by the action of an acidto give a compound of formula (I″):

and c) the compound of formula (I″) is reacted with ethylamine,dimethylamine or azetidine.
 9. A compound of formula (II):

in which: n is 1 or 2; W represents an oxygen atom or a sulphur atom; R₁represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; or a trifluoromethoxy radical; R₂ represents ahydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; or atrifluoromethyl radical; or R₂ is in position -6- of the indol-2-onering and R₁ and R₂ together represent a divalent trimethylene radical;R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; or a trifluoromethoxy radical; R₄ represents a hydrogenatom; a halogen atom; a (C₁-C₂)alkyl; or a (C₁-C₂)alkoxy; or R₃ is inposition -2- of the phenyl, R₄ is in position -3- of the phenyl and R₃and R₄ together represent a methylenedioxy radical; and R₅ represents anethylamino group; a dimethylamino group; a 1-azetidinyl radical; or a(C₁-C₂)alkoxy; or a salt thereof with mineral or organic acids. 10-12.(canceled)
 13. A compound according to claim 3 in which: n is 2; Wrepresents an oxygen atom; R₁ represents a chlorine atom or a methylradical; R₂ represents a hydrogen atom or is in position -6- of theindol-2-one and represents a chlorine atom, a methyl radical, a methoxyradical or a trifluoromethyl radical; R₃ is in position -2- of thephenyl and represents a methoxy radical, a chlorine atom or a fluorineatom; R₄ represents a hydrogen atom, a methyl radical or a methoxyradical; or R₃ is in position -2- of the phenyl, R₄ is in position -3-of the phenyl and R₃ and R₄ together represent a methylenedioxy radical;R₅ represents a dimethylamino group or a methoxy radical; R₆ is inposition -2- of the phenyl and represents a methoxy radical; R₇represents a methoxy radical; and or a solvate or hydrate thereof.
 14. Acompound according to claim 4 in which: n is 2; W represents an oxygenatom; R₁ represents a chlorine atom or a methyl radical; R₂ represents ahydrogen atom or is in position -6- of the indol-2-one and represents achlorine atom, a methyl radical, a methoxy radical or a trifluoromethylradical; R₃ is in position -2- of the phenyl and represents a methoxyradical, a chlorine atom or a fluorine atom; R₄ represents a hydrogenatom, a methyl radical or a methoxy radical; or R₃ is in position -2- ofthe phenyl, R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical; R₅ represents a dimethylamino groupor a methoxy radical; R₆ is in position -2- of the phenyl and representsa methoxy radical; R₇ represents a methoxy radical; and or a solvate orhydrate thereof.
 15. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable excipient.
 16. Apharmaceutical composition comprising a compound according to claim 5and a pharmaceutically acceptable excipient.
 17. A pharmaceuticalcomposition comprising a compound according to claim 6 and apharmaceutically acceptable excipient.
 18. A pharmaceutical compositioncomprising a compound according to claim 13 and a pharmaceuticallyacceptable excipient.
 19. A method of treatment of a pathology in whicharginine-vasopressin and/or its V_(1b) receptors or both its V_(1b) andV_(1a) receptors are involved which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 1. 20. A method of treatment of a pathologyin which arginine-vasopressin and/or its V_(1b) receptors or both itsV_(1b) and V_(1a) receptors are involved which comprises administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound according to claim
 5. 21. A method of treatment ofa pathology in which arginine-vasopressin and/or its V_(1b) receptors orboth its V_(1b) and V_(1a) receptors are involved which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 6. 22. A method oftreatment of a pathology in which arginine-vasopressin and/or its V_(1b)receptors or both its V_(1b) and V_(1a) receptors are involved whichcomprises administering to a patient in need of such treatment atherapeutically effective amount of a compound according to claim 13.